Method of treating a PAF-mediated pathology or for treating or preventing psoriasis, nephritis, asthma or shock by administering a PAF antagonist

ABSTRACT

A method of treating a PAF-mediated pathology or for treating or preventing psoriasis, nephritis, asthma, inflammation or shock by administering an effective amount of a PAF antagonist of the formula ##STR1## wherein R 1  and R 2  are each --R 5 , --CH═CH--R 5  or --C.tbd.C--R 5  ; R 5  is an unsubstituted or substituted C 6  -C 14  carbocyclic aryl of an aromatic heterocyclic having from 5 to 14 ring atoms, of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur, the heterocyclic group being unsubstituted or substituted; R 3  is hydrogen, a C 1  -C 6  alkyl, cyano, or --R 5  ; X is oxygen or sulfur; A is a 1,4-piperazin-1,4-diyl or a 1,4-homopiperazin-1,4-diyl; B is a C 1  -C 6  alkylene, carbonyl, thiocarbonyl, sulfinyl or sulfonyl; and R 4  is an unsubstituted or substituted phenyl group.

This is a division of application Ser. No. 07/973,086 filed Nov. 6,1992, now U.S. Pat. No. 5,369,106, which is a division of applicationSer. No. 07/751,871 filed Aug. 28, 1991, now U.S. Pat. No. 5,192,766,which is a continuation-in-part of application Ser. No. 07/514,523 filedApr. 25, 1990 (abandoned).

BACKGROUND OF THE INVENTION

The present invention relates to a series of novel N-acryloylpiperazinederivatives which have PAF antagonist activity and provides processesfor preparing these derivatives, as well as methods and compositionsusing them for the treatment of various diseases and disorders arisingfrom imbalances in the PAF system in the mammalian, e.g. human, body.

The abbreviation "PAF" as used herein means, as is conventional,"platelet activating factor".

Natural PAF, at least as isolated from mammalian tissues, is a mixtureof from 2 to 5 phospholipids, the number depending upon the nature ofthe original tissue. The formulae of the major constituents of PAF arenow well known. Natural PAF is levorotatory and the various componentsof natural PAF may be identified, for example as: l-C_(16:0) =PAF wherethe alkoxy group at the PAF 1-position is a hexadecyloxy group;l-C_(18:0) =PAF where the alkoxy group at the PAF 1-position is anoctadecyloxy group; or l-C_(18:1) =PAF where the alkoxy group at the PAF1-position is a 9-(Z)-octadecenyloxy group. The convention used abovefor identifying the constituents of PAF gives the rotation first (l, inthe above examples), followed by the number of carbon atoms in the1-alkoxy group, and finally the number of double bonds.

PAF exhibits a strong platelet activating and aggregating effect, fromwhich it derives its name. It has, however, in recent years been seen tobe a potentially crucial mediator in a wide variety of pathologicalprocesses. Thus, it also has a hypotensive effect and increasesvasopermeability; it is believed to be an active agent in the inductionof the shock state (for example endotoxin-induced shock or anaphylacticshock) and to act as a mediator of inflammatory disease. It has alsobeen found to play an important role in nephritis, myocardialinfarction, angina pectoris, asthma, cardiac and systemic anaphylaxis,gastric and intestinal ulceration, psoriasis and immune and renaldisorders. In addition, it is believed that PAF antagonists may beuseful for prophylaxis of rejection in organ transplantation.

It is not, therefore, surprising that, as a result, PAF antagonists havebeen investigated with a view to developing new types of treatment forthe above pathologies, and notably new types of anti-shock agent andanti-inflammatory agent. Accordingly, various compounds have beeninvestigated in an attempt to find such PAF antagonists, and, currently,several compounds are known as PAF antagonists. Although the chemicalstructure of known PAF antagonists varies widely, and there appears tobe no obvious common factor linking all of their chemical structures, ingeneral, known materials having PAF-antagonist activity may beclassified according to their chemical structure as either PAF type ornon-PAF type compounds. The compounds of the present invention arenon-PAF type compounds, and specifically are compounds containing anN-acryloylpiperazine or N-acryloylhomopiperazine system.

Amongst known such compounds which have structures similar to those ofthe compounds of present invention and which are said to have similartypes of activities are:

the pentadienylamido compounds disclosed, inter alia, in U.S. Pat. No.4,788,206;

the alkenyl-, alkenoyl- or thioalkenoyl- amido compounds disclosed,inter alia, in European Patent Publication No. 298 466; and

the polycycloalkylcarbonyl- piperazine or homopiperazine compoundsdisclosed, inter alia, in European Patent Publication No. 284 359.

Also known are the N-nicotinoylpiperazine derivatives of Japanese PatentApplication Kokai No. Sho. 60-193966, but these are only disclosed tohave peripheral vasodilating and anti-hypertensive activities, and thereis no suggestion that the compounds are PAF antagonists.

The compounds of the prior art referred to above all have structuresdifferent from those of the compounds of the present invention,although, in some cases, the prior compounds may share elements of thestructures of the compounds of the present invention. In particular,none of the prior compounds is an N-acryloylpiperazine orN-acryloylhomopiperazine compound.

We have now discovered a series of new N-acryloylpiperazine andN-acryloylhomopiperazine derivatives which have excellent PAF antagonistactivity and many of which have shown an excellent and wholly unexpectedstability, even when administered orally, to give a high bloodconcentration. The activities of many of the compounds of the presentinvention have shown indications of being substantially better thanthose of the compounds of the prior art, including those referred toabove and having structures similar to those of the compounds of thepresent invention.

BRIEF SUMMARY OF INVENTION

Accordingly, it is an object of the present invention to provide aseries of new N-acryloylpiperazine derivatives as a new composition ofmatter.

It is a further, and more specific, object of the invention to providesuch N-acryloylpiperazine derivatives having improved PAF antagonistactivity and preferably stability on oral administration to a mammal.

It is a still further object of the invention to provide compositionscontaining these compounds and methods using them for the treatment andprophylaxis of PAF-related diseases and disorders.

Other objects and advantages will become apparent as the descriptionproceeds.

In accordance with the present invention, there are provided as newcompounds those acryloylpiperazine and acryloylhomopiperazine compoundshaving the formula (I): ##STR2## wherein: R¹ and R² are the same ordifferent, and each represents a group having the formula --R⁵,--CH═CH--R⁵ or --C.tbd.C--R⁵, wherein R⁵ represents a C₆ -C₁₄carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (a),defined below, or an aromatic heterocyclic group having from 5 to 14ring atoms, of which from 1 to 5 are hetero-atoms selected from thegroup consisting of nitrogen, oxygen and sulfur hetero-atoms, saidheterocyclic group being unsubstituted or having at least onesubstituent selected from the group consisting of substituents (a),defined below;

R³ represents a hydrogen atom, a C₁ -D₆ alkyl group, a cyano group, or agroup having the formula --R⁵, in which R⁵ is as defined above;

X represents an oxygen atom or a sulfur atom;

A represents a 1,4-piperazin-1,4-diyl group or a1,4-homopiperazin-1,4-diyl group;

B' represents a C₁ -C₆ alkylene group, a carbonyl group, a thiocarbonylgroup, a sulfinyl group or a sulfonyl group;

R⁴ represents an unsubstituted phenyl group or a substituted phenylgroup having from 1 to 5 substituents selected from the group consistingof substituents (a) and substituents (b), defined below;

substituents (a):

C₁ -C₂₂ alkyl groups; C₁ -C₂₂ alkoxy groups;

C₁ -C₆ haloalkyl groups; hydroxy groups;

C₁ -C₄ alkylenedioxy groups; C₁ -C₂₂ aliphatic carboxylic acyloxygroups; substituted C₁ -C₆ aliphatic carboxylic acyloxy groups having atleast one substituent selected from the group consisting of substituents(c), defined below; C₇ -C₁₅ carbocyclic aromatic carboxylic acyloxygroups; substituted C₇ -C₁₅ carbocyclic aromatic carboxylic acyloxygroups having at least one substituent selected from the groupconsisting of substituents (d), defined below; C₈ -C₁₅aralkyloxycarbonyloxy groups in which the aryl part is unsubstituted orhas at least one substituent selected from the group consisting ofsubstituents (d), defined below; C₁ -C₆ alkanesulfonyloxy groups inwhich the alkane part is unsubstituted or has at least one substituentselected from the group consisting of substituents (c), defined below;arylsulfonyloxy groups in which the aryl part is unsubstituted or has atleast one substituent selected from the group consisting of substituents(d), defined below; halogen atoms; and nitro groups;

substituents (b):

C₁ -C₆ alkylsulfonyl groups; C₁ -C₆ alkylsulfinyl groups; and C₁ -C₆alkylthio groups;

substituents (c):

C₁ -C₆ alkyl groups; C₁ -C₆ haloalkyl groups; halogen atoms; C₁ -C₆alkoxy groups; and (C₁ -C₆ alkanoyloxy)methoxycarbonyl groups;

substituents (d):

C₁ -C₆ alkyl groups; C₁ -C₆ alkoxy groups; halogen atoms; unsubstitutedC₆ -C₁₀ aryl groups; nitro groups; and (C₁ -C₆ alkoxy)carbonyl groups;

and pharmaceutically acceptable salts thereof.

The invention also provides a pharmaceutical composition for thetreatment or prophylaxis of PAF-related diseases and disorders,comprising at least one PAF antagonist in combination with apharmaceutically acceptable carrier or diluent, wherein the PAFantagonist is selected from the group consisting of compounds of formula(I), as defined above, and pharmaceutically acceptable salts thereof.

The invention still further provides a method of treating a PAF-mediatedpathology in a mammal susceptible to such pathology, which may be ahuman being, by administering to said mammal an effective amount of atleast one PAF antagonist selected from the group consisting of acompound of formula (I), as defined above, and pharmaceuticallyacceptable salts thereof.

The invention still further provides a method for the treatment orprophylaxis of psoriasis, nephritis, asthma, inflammation or shockcomprising administering an amount of at least one PAF antagonist to ananimal (which may be a mammal, e.g. human) sufficient to effecttreatment or prophylaxis of psoriasis, nephritis, asthma, inflammationor shock, wherein said PAF antagonist is selected from the groupconsisting of a compound of formula (I), as defined above. andpharmaceutically acceptable salts thereof.

The invention also provides processes for the preparation of thecompounds of the present invention, which are described in greaterdetail hereafter.

DETAILED DESCRIPTION OF INVENTION

In the compounds of the present invention R¹ and R² are the same ordifferent and each represents a group of formula --R⁵, --CH═CH--R⁵ or--C.tbd.C--R⁵, where R⁵ is as defined above.

Where R⁵ represents an aryl group, this is a carbocyclic aryl groupwhich has from 6 to 14, preferably from 6 to 12 and more preferably from6 to 10, ring carbon atoms, and which may be substituted orunsubstituted. Where the group is substituted, the substituents areselected from the group consisting of substituents (a), defined aboveand exemplified below. Examples of such unsubstituted groups include thephenyl and naphthyl (1- or 2-naphthyl) groups, preferably the phenylgroup.

It is believed that the nature of the substituents on the phenyl groupsrepresented by R⁵, which may be or may be included in the groupsrepresented by R¹ and R², may have a significant effect on the efficacyof the compounds of the present invention, although the exact nature ofthis effect has not been fully elucidated. In general, we prefer thosecompounds where R¹ and/or R² represents a group R⁵, and more preferthose where R¹ and/or R² represents a group R⁵ where R⁵ represents anaryl group; most preferably one of the groups represented by R⁵ is asubstituted phenyl group and the other is an unsubstituted phenyl groupor a substituted phenyl group. Still more preferably, in the group R⁵represented by or included in the group represented by R¹, there is anelectron-donating substituent (e.g. a methoxy group) or anelectron-withdrawing substituent (e.g. a chlorine atom) on the arylgroup; and, in the group R⁵ represented by or included in the grouprepresented by R², there is no substituent, an alkyl substituent or anelectron-withdrawing substituent on the aryl group. This applies evenwhen R¹ and/or R² represents a group of formula --CH═CH--R⁵ or--C.tbd.C--R⁵, but these compounds are most preferred when R¹ and R² aredifferent and both represent a group of formula --R⁵.

Where R² represents a substituted phenyl group, it is preferablysubstituted at least at the meta-position.

Examples of groups and atoms which may be included within substituents(a) are:

C₁ -C₂₂ alkyl groups, which may be straight or branched chain groups,such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, hexyl,4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 3,3-dimethylbutyl,2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, t-pentyl, isohexyl,1-methylpentyl, heptyl, 1-methylhexyl, 2-methylhexyl, 5-methylhexyl,3-ethylpentyl, octyl, 2-methylheptyl, 5-methylheptyl, 2-ethylhexyl,2-ethyl-3-methylpentyl, 3-ethyl-2-methylpentyl, nonyl, 2-methyloctyl,7-methyloctyl, 4-ethylheptyl, 3-ethyl-2-methylhexyl,2-ethyl-1-methylhexyl, decyl, 2-methylnonyl, 8-methylnonyl,5-ethyloctyl, 3-ethyl-2-methylheptyl, 3,3-diethylhexyl, undecyl,2-methyldecyl, 9-methyldecyl, 4-ethylnonyl, 3,5-dimethylnonyl,3-propyloctyl, 5-ethyl-4-methyloctyl, dodecyl, 1-methylundecyl,10-methylundecyl, 3-ethyldecyl, 5-propylnonyl, 3,5-diethyloctyl,tridecyl, 11-methyldodecyl, 7-ethylundecyl, 4-propyldecyl,5-ethyl-3-methyldecyl, 3-pentyloctyl, tetradecyl, 12-methyltridecyl,8-ethyldodecyl, 6-propylundecyl, 4-butyldecyl, 2-pentylnonyl,pentadecyl, 13-methyltetradecyl, 10-ethyltridecyl, 7-propyldodecyl,5-ethyl-3-methyldodecyl, 4-pentyldecyl, hexadecyl, 14-methylpentadecyl,6-ethyltetradecyl, 4-propyltridecyl, 2-butyldodecyl, heptadecyl,15-methylhexadecyl, 7-ethylpentadecyl, 3-propyltetradecyl,5-pentyldodecyl, octadecyl, 16-methylheptadecyl, 5-propylpentadecyl,nonadecyl, 17-methyloctadecyl, 4-ethylheptadecyl, icosyl,18-methylnonadecyl, 3-ethyloctadecyl, henicosyl and docosyl groups,preferably a straight or branched chain alkyl group having from 1 to 6carbon atoms, and more preferably a straight or branched chain alkylgroup having from 1 to 4 carbon atoms;

C₁ -C₂₂ alkoxy groups, which may be straight or branched chain groups,such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy,hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy,3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, t-pentoxy,isohexyloxy, 1-methylpentoxy, heptyloxy, 1-methylhexyloxy,2-methylhexyloxy, 5-methylhexyloxy, 3-ethylpentoxy, octyloxy,2-methylheptyloxy, 5-methylheptyloxy, 2-ethylhexyloxy,2-ethyl-3-methylpentoxy, 3-ethyl-2-methylpentoxy, nonyloxy,2-methyloctyloxy, 7-methyloctyloxy, 4-ethylheptyloxy,3-ethyl-2-methylhexyloxy, 2-ethyl-1-methylhexloxy, decyloxy,2-methylnonyloxy, 8-methylnonyloxy, 5-ethyloctyloxy,3-ethyl-2-methylheptyloxy, 3,3-diethylhexyloxy, undecyloxy,2-methyldecyloxy, 9-methyldecyloxy, 4-ethylnonyloxy,3,5-dimethylnonyloxy, 3-propyloctyloxy, 5-ethyl-4-methyloctyloxy,dodecyloxy, 1-methylundecyloxy, 10-methylundecyloxy, 3-ethyldecyloxy,5-propylnonyloxy, 3,5-diethyloctyloxy, tridecyloxy, 11-methyldodecyloxy,7-ethylundecyloxy, 4-propyldecyloxy, 5-ethyl-3-methyldecyloxy,3-pentyloctyloxy, tetradecyloxy, 12-methyltridecyloxy,8-ethyldodecyloxy, 6-propylundecyloxy, 4-butyldecyloxy,2-pentylnonyloxy, pentadecyloxy, 13-methyltetradecyloxy,10-ethyltridecyloxy, 7-propyldodecyloxy, 5-ethyl-3-methyldodecyloxy,4-pentyldecyloxy, hexadecyloxy, 14-methylpentadecyloxy,6-ethyltetradecyloxy, 4-propyltridecyloxy, 2-butyldodecyloxy,heptadecyloxy, 15-methylhexadecyloxy, 7-ethylpentadecyloxy,3-propyltetradecyloxy, 5-pentyldodecyloxy, octadecyloxy,16-methylheptadecyloxy, 5-propylpentadecyloxy, nonadecyloxy,17-methyloctadecyloxy, 4-ethylheptadecyloxy, icosyloxy,18-methylnonadecyloxy, 3-ethyloctadecyloxy, henicosyl and docosylgroups, preferably a straight or branched chain alkoxy group having from1 to 6 carbon atoms, and more preferably a straight or branched chainalkoxy group having from 1 to 4 carbon atoms;

C₁ -C₆ haloalkyl groups, in which the alkyl part may be any one of thosealkyl groups exemplified above, and is more preferably a C₁ -C₄ alkylgroup, and the halogen atom may be a fluorine, chlorine, bromine oriodine atom, preferably a fluorine or chlorine atom, such as thefluoromethyl, trifluoromethyl, difluoromethyl, dichloromethyl,dibromomethyl, trichloromethyl, 2,2,2-trichloroethyl,2,2,2-trifluoroethyl, 2-haloethyl (e.g. 2-chloroethyl, 2-fluoroethyl,2-bromoethyl or 2-iodoethyl), 2,2-dibromoethyl, 2,2,2-tribromoethyl,pentafluoroethyl, 4-chlorobutyl, 4-bromobutyl and 4-fluorobutyl groups,preferably the trifluoromethyl, trichloromethyl and pentafluoroethylgroups;

hydroxy groups;

C₁ -C₄ alkylenedioxy groups in which the alkylene part may be a straightor branched chain group; examples include the methylenedioxy,dimethylenedioxy, trimethylenedioxy, tetramethylenedioxy,ethylidenedioxy and isopropylidenedioxy groups, of which themethylenedioxy group is preferred;

unsubstituted C₁ -C₂₂ aliphatic carboxylic acyloxy groups, in which theacyl part may contain one or more carbon-carbon double or triple bondsor may be free from such bonds, and in the case of the unsaturatedgroups, the number of carbon atoms is preferably from 3 to 6; examplesof such groups include the alkanoyloxy groups, such as the formyloxy,acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy,valeryloxy, isovaleryloxy, octanoyloxy, nonylcarbonyloxy,decylcarbonyloxy, 3-methylnonylcarbonyloxy, 8-methylnonylcarbonyloxy,3-ethyloctylcarbonyloxy, 3,7-dimethyloctylcarbonyloxy,undecylcarbonyloxy, dodecylcarbonyloxy, tridecylcarbonyloxy,tetradecylcarbonyloxy, pentadecylcarbonyloxy, hexadecylcarbonyloxy,1-methylpentadecylcarbonyloxy, 14-methylpentadecylcarbonyloxy,13,13-dimethyltetradecylcarbonyloxy, heptadecylcarbonyloxy,15-methylhexadecylcarbonyloxy, octadecylcarbonyloxy,1-methylheptadecylcarbonyloxy, nonadecylcarbonyloxy, icosylcarbonyloxyand henicosylcarbonyloxy groups; unsaturated analogs of thesealkanoyloxy groups, especially the C₃ -C₆ alkenoyloxy and alkynoyloxygroups, such as the (E)-2-methyl-2-butenoyloxy group; alkoxycarbonyloxygroups, especially C₂ -C₇ alkoxycarbonyloxy groups (i.e. the alkoxy partis C₁ -C₆), such as the methoxycarbonyloxy, ethoxycarbonyloxy,t-butoxycarbonyloxy and isobutoxycarbonyloxy groups; suchalkoxycarbonyloxy groups having one or more halogen or trialkylsilylsubstituents (in which each alkyl group, which may be the same ordifferent, has from 1 to 4 carbon atoms, and in which one such alkylgroup may be replaced by a phenyl group), such as the2,2,2-trichloroethoxycarbonyloxy and 2-trimethylsilylethoxycarbonyloxygroups; and the alkenyloxycarbonyloxy groups, such as thevinyloxycarbonyloxy and allyloxycarbonyloxy groups;

substituted C₁ -C₆ aliphatic carboxylic acyloxy groups having at leastone substituent selected from the group consisting of substituents (c),defined above and exemplified more generally below; the acyloxy part maybe any of the C₁ -C₆ unsubstituted acyloxy groups exemplified above, andspecific examples of the substituted groups include: the halogenatedalkanoyloxy groups, such as the chloroacatoxy, dichloroacatoxy,trichloroacetoxy and trifluoroacetoxy groups; the alkoxyalkanoyloxygroups, such as the methoxyacetoxy group; and the (C₁ -C₆alkanoyloxy)methoxycarbonyl groups, such as thepivaloyloxymethoxycarbonyloxy group;

C₇ -C₁₅, preferably C₇ -C₁₁, carbocyclic aromatic carboxylic acyloxygroups (i.e. an arylcarbonyl group in which the aryl part is C₆ -C₁₄,preferably C₆ -C₁₀), which may be unsubstituted or may have one or moresubstituents selected from the group consisting of substituents (d),defined above and exemplified more generally below; examples of suchunsubstituted groups include the benzoyloxy, α-naphthoyloxy andβ-naphthoyloxy groups; the substituted groups may be any of theseunsubstituted groups but having at least one, and preferably from 1 to5, more preferably from 1 to 3, substituents selected from the groupconsisting of substituents (d); examples of the substituted groupsinclude: halogenated arylcarbonyloxy groups, such as the2-bromobenzoyloxy and 4-chlorobenzoyloxy groups; arylcarbonyloxy groupssubstituted by one or more lower (i.e. C₁ -C₆, preferably C₁ -C₄) alkylgroups, such as the 2, 4, 6-trimethylbenzoyloxy and p-toluoyloxy groups;arylcarbonyloxy groups substituted by one or more lower (i.e. C₁ -C₆,preferably C₁ -C₄) alkoxy groups, such as the 4-anisoyloxy group;arylcarbonyloxy groups substituted by one or more nitro groups, such asthe 4-nitrobenzoyloxy and 2-nitrobenzoyloxy groups; arylcarbonyloxygroups substituted by one or more lower (i.e. C₂ -C₇, preferably C₂ -C₅)alkoxycarbonyl groups, such as the 2-(methoxycarbonyl)benzoyloxy group;and arylcarbonyloxy groups substituted by one or more aryl groups, suchas the 4-phenylbenzoyloxy

C₈ -C₁₅ aralkyloxycarbonyloxy groups in which the aryl part is C₆ -C₁₀and the alkyl part is correspondingly C₁ -C₄ ; these groups may beunsubstituted or may have at least one substituent, preferably on thearyl part or parts, selected from the group consisting of substituents(d), defined above and exemplified more generally below, preferably oneor two lower alkoxy or nitro groups; the alkyl part is preferablyunsubstituted; examples of such unsubstituted groups include thebenzyloxycarbonyloxy group; and examples of such substituted groupsinclude the unsubstituted groups referred to but having one or more,preferably from 1 to 5, more preferably from 1 to 3, of substituents(d), such as the 4-methoxybenzyloxycarbonyloxy, 3,4-dimethoxybenzyloxycarbonyloxy, 2-nitrobenzyloxycarbonyloxy and4-nitrobenzyloxycarbonyloxy groups;

C₁ -C₆ alkanesulfonyloxy groups in which the alkane part isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (c), defined above and exemplified moregenerally below, preferably halogen atoms and more preferably fluorineatoms; examples of such groups include the lower (i.e. C₁ -C₆,preferably C₁ -C₄) alkanesulfonyloxy groups, such as themethanesulfonyloxy, ethanesulfonyloxy and 1-propanesulfonyloxy groups;and fluorinated lower alkanesulfonyloxy groups, such as thetrifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy groups;

arylsulfonyloxy groups in which the aryl part is C₆ -C₁₀ and may beunsubstituted or may have at least one substituent selected from thegroup consisting of substituents (d), defined above and exemplified moregenerally below; examples of such unsubstituted groups include thebenzenesulfonyloxy group, and examples of such substituted groupsinclude the unsubstituted groups referred to but having one or more,preferably from 1 to 5, more preferably from 1 to 3, of substituents(d), such as the p-toluenesulfonyloxy group;

halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms,preferably the fluorine, chlorine and bromine atoms; and

nitro groups.

Where substituent (a) is one of the aforementioned acyloxy groups, itmay, if desired, be an acyloxy group which is easily hydrolysed in vivo,so as to form a pro-drug, which may be administered as the ester[substituent (a) is the acyloxy group], and is then converted to thefree acid [substituent (a) is a hydroxy group], in vivo. Examples ofsuch groups include: the (C₁ -C₆ alkanoyloxy)methoxycarbonyl groups,especially the pivaloyloxymethoxycarbonyloxy group; thealkanesulfonyloxy groups, especially the methanesulfonyloxy,ethanesulfonyloxy and 1-propanesulfonyloxy groups; the fluorinatedalkanesulfonyloxy groups, especially the trifluoromethanesulfonyloxy andpentafluoroethanesulfonyloxy groups; and the arylsulfonyloxy groups,especially the benzenesulfonyloxy and p-toluenesulfonyloxy groups.

Examples of groups and atoms included in substituents (c) are:

the C₁ -C₆, preferably C₁ -C₄, alkyl groups, such as those exemplifiedabove in relation to substituents (a);

the C₁ -C₆, preferably C₁ -C₄, haloalkyl groups, such as thoseexemplified above in relation to substituents (a), and especially thetrifluoromethyl and pentafluoroethyl groups;

halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms,especially the chlorine and fluorine atoms;

the C₁ -C₆, preferably C₁ -C₄, alkoxy groups, such as those exemplifiedabove in relation to substituents (a), and especially the methoxy group;and

the (C₁ -C₆ alkanoyloxy)methoxycarbonyl groups, such as theformyloxymethoxycarbonyl, acetoxymethoxycarbonyl,propionyloxymethoxycarbonyl, butyryloxymethoxycarbonyl,isobutyryloxymethoxycarbonyl, pivaloyloxymethoxycarbonyl,valeryloxymethoxycarbonyl and isovaleryloxymethoxycarbonyl groups,especially the pivaloyloxymethoxycarbonyloxy group.

Examples of groups and atoms included in substituents (d) are:

the C₁ -C₆, preferably C₁ -C₄, alkyl groups, such as those exemplifiedabove in relation to substituents (a);

the C₁ -C₆, preferably C₁ -C₄, alkoxy groups, such as those exemplifiedabove in relation to substituents (a), and especially the methoxy group;

halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms,especially the chlorine and fluorine atoms;

C₆ -C₁₀ aryl groups which are not substituted, such as the phenyl ornaphthyl groups;

the nitro group; and

C₂ -C₇ alkoxycarbonyl groups (i.e. the alkoxy part is C₁ -C₆), such asthe methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl andisobutoxycarbonyl groups.

Examples of aromatic heterocyclic groups which may be represented by R⁵include aromatic 5- to 14-membered heterocyclic groups, which may bemonocyclic or condensed ring polycyclic groups, and whose ring atomsinclude from 1 to 5, preferably from 1 to 3, sulfur and/or oxygen and/ornitrogen atoms. Such groups have at least one ring having aromaticcharacter, and, where there are two or more rings, these preferably, butnot necessarily, all have aromatic character. Where the group is acondensed ring system, at least one of the rings must be a heterocyclicring, and the other or others may be heterocyclic or non-heterocyclic,e.g. a benzene ring. Examples of such groups include the furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl,thiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl,purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,carbolinyl, phenanthridinyl and acridinyl groups. Of these, we preferthe aromatic 5- to 10-membered heterocyclic groups, which may optionallybe condensed, having 1 or 2 sulfur and/or oxygen and/or nitrogen atoms,and more preferably the furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl,pyridyl, quinolyl and isoquinolyl groups.

We most prefer that R¹ should represent a substituted phenyl grouphaving at least one of the aforementioned alkyl, alkoxy or halogensubstituents and that R² should represent an unsubstituted phenyl groupor a substituted phenyl group having at least one substituent selectedfrom the group consisting of the aforementioned alkyl, haloalkyl andhalogen substituents.

Examples of the C₁ -C₆ alkyl groups which may be represented by R³include those groups referred to above in relation to the alkyl groupswhich may be included within substituents (a), of which the straight andbranched chain alkyl groups having 1 to 4 carbon atoms are preferred.

R³ may also represent any of the groups defined and exemplified abovefor R⁵, or it may represent a cyano group or a hydrogen atom, but it ispreferably a hydrogen atom.

X may represent an oxygen or sulfur atom, but is preferably an oxygenatom.

Where B' represents an alkylene group, this has from 1 to 6 carbonatoms, and examples include the methylene, methylmethylene, ethylene,propylene, trimethylene, tetramethylene, 1-methyltrimethylene,2-methyltrimethylene, 3-methyltrimethylene, pentamethylene andhexamethylene groups, of which the methylene, ethylene, trimethylene andtetramethylene groups are preferred.

B' may also represent a carbonyl group, a thiocarbonyl (>C═S) group, asulfonyl (>SO₂) group or a sulfinyl (>SO) group. Most preferably Brepresents a carbonyl group.

R⁴ represents a phenyl group which may be unsubstituted or may have atleast one substituent selected from the group consisting of substituents(a) and (b). Substituents (a) are both defined and exemplified above.Substituents (b) are defined above, and examples include:

lower alkylsulfonyl groups, which may have from 1 to 6, preferably from1 to 4, carbon atoms in the alkyl part thereof, and which may be astraight or branched chain group such as those exemplified in relationto the alkyl group which may be included in substituents (a); examplesof preferred such alkanesulfonyl groups include the methanesulfonyl,ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl,isobutanesulfonyl, sec-butanesulfonyl, t-butanesulfonyl,pentanesulfonyl, isopentanesulfonyl, 2-methylbutanesulfonyl,neopentanesulfonyl, hexanesulfonyl, 4-methylpentanesulfonyl,3-methylpentanesulfonyl, 2-methylpentanesulfonyl,3,3-dimethylbutanesulfonyl, 2,2-dimethylbutanesulfonyl,1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl,1,3-dimethylbutanesulfonyl and 2,3-dimethylbutanesulfonyl groups, ofwhich the straight and branched chain alkanesulfonyl groups having from1 to 4 carbon atoms are preferred;

lower alkylsulfinyl groups, which may have from 1 to 6, preferably from1 to 4, carbon atoms in the alkyl part thereof, and which may be astraight or branched chain group such as those exemplified in relationto the alkyl group which may be included in substituents (a); examplesof preferred such alkanesulfinyl groups include the methanesulfinyl,ethanesulfinyl, propanesulfinyl, isopropanesulfinyl, butanesulfinyl,isobutanesulfinyl, sec-butanesulfinyl, t-butanesulfinyl,pentanesulfinyl, isopentanesulfinyl, 2-methylbutanesulfinyl,neopentanesulfinyl, hexanesulfinyl, 4-methylpentanesulfinyl,3-methylpentanesulfinyl, 2-methylpentanesulfinyl,3,3-dimethylbutanesulfinyl, 2,2-dimethylbutanesulfinyl,1,1-dimethylbutanesulfinyl, 1,2-dimethylbutanesulfinyl,1,3-dimethylbutanesulfinyl and 2,3-dimethylbutanesulfinyl groups, ofwhich the straight and branched chain alkanesulfinyl groups having from1 to 4 carbon atoms are preferred; and

lower alkylthio groups, which may have from 1 to 6, preferably from 1 to4, carbon atoms in the alkyl part thereof, which may be straight orbranched chain group such as those exemplified in relation to the alkylgroup which may be included in substituents (a); examples of preferredsuch alkylthio groups include the methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio,pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio,4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio,3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio,1,2-dimethylbutylthio, 1,3-dimethylbutylthio and 2,3-dimethylbutylthiogroups, of which the straight and branched chain alkylthio groups havingfrom 1 to 4 carbon atoms are preferred.

We most prefer those compounds of the present invention in which R⁴represents a phenyl group having at least one C₁ -C₃ alkoxy, morepreferably methoxy, substituent, and most preferred are those compoundswhere R⁴ represents a 3,4-dimethoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl or 3,4,5-trimethoxyphenyl group.

Certain of the compounds of the present invention can form salts. Thereis no particular restriction on the nature of these salts, providedthat, where they are intended for therapeutic use, they arepharmaceutically acceptable. Where they are intended for non-therapeuticuses, e.g. as intermediates in the preparation of other, and possiblymore active, compounds, even this restriction does not apply. Thecompounds may include at least one basic nitrogen atom, where 3represents a C₁ -C₆ alkylene group, and can, therefore, form acidaddition salts. Examples of such acid addition salts include: salts witha mineral acid, especially a hydrogen halide (such as hydrofluoric acid,hydrochloric acid, hydrobromic acid or hydroiodic acid), nitric acid,perchloric acid, sulfuric acid or phosphoric acid; salts with an organiccarboxylic acid, such as fumaric acid, succinic acid, citric acid,tartaric acid, oxalic acid, maleic acid or malic acid; salts with asulfonic acid, especially a lower alkanesulfonic acid (such asmethanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonicacid) or an arylsulfonic acid (such as benzenesulfonic acid orp-toluenesulfonic acid); and salts with an amino acid, such as glutamicacid and aspartic acid.

The compounds of the present invention may contain several asymmetriccarbon atoms in their molecules, and can thus form optical isomershaving the (R)-configuration or the (S)-configuration. Also, because ofthe carbon-carbon double bond, they can exist in the form of geometricisomers, i.e. the (Z)-isomer or the (E)-isomer. Although these are allrepresented herein by a single molecular formula, the present inventionincludes both the individual, isolated isomers and mixtures, includingracemates thereof. Where stereospecific synthesis techniques areemployed, individual isomers may be prepared directly; on the otherhand, if a mixture of isomers is prepared, the individual isomers may beobtained by conventional resolution techniques.

Of the compounds of the present invention, the following are preferred:

(1) Compounds in which both R¹ and R² are independently selected fromthe group consisting of groups represented by --R⁵ (in which R⁵ is asdefined above);

(2) Compounds in which at least one of R¹ and R² represents an arylgroup having at least one substituent selected from the group consistingof substituents (a), defined above;

(3) Compounds in which R³ represents a hydrogen atom or a C₁ -C₆ alkylgroup;

(4) Compounds in which R⁴ represents a substituted phenyl group havingfrom 1 to 5 C₁ -C₆ alkoxy substituents;

(5) Compounds in which X represents an oxygen atom;

(6) Compounds in which A represents a 1,4-piperazin-1,4-diyl group.

More preferred are those compounds in which R¹ and R² are as defined in(1) or (2) above, R³ is as defined in (3) above, R⁴ is as defined in (4)above, X is as defined in (5) above and A is as defined in (6) above.

Still more preferred are those compounds in which:

(7) R¹ represents a substituted phenyl group having at least one C₁ -C₂₂alkyl, C₁ -C₂₂ alkoxy or halogen substituent;

(8) R¹ represents a substituted phenyl group having at least one C₁ -C₆alkyl, C₁ -C₆ alkoxy or halogen substituent;

(9) R² represents an unsubstituted phenyl group or a substituted phenylgroup having at least one substituent selected from the group consistingof C₁ -C₂₂ alkyl groups, C₁ -C₂₂ alkoxy groups, C₁ -C₆ haloalkyl groupsand halogen atoms;

(10) R² represents a substituted phenyl group having at least onesubstituent selected from the group consisting of C₁ -C₂₂ alkyl groups,C₁ -C₂₂ alkoxy groups, C₁ -C₆ haloalkyl groups and halogen atoms;

(11) R² represents a substituted phenyl group having at least onesubstituent selected from the group consisting of C₁ -C₂₂ alkyl groups,C₁ -C₆ haloalkyl groups and halogen atoms;

(12) R² represents a substituted phenyl group having at least onesubstituent selected from the group consisting of C₁ -C₆ alkyl groups,C₁ -C₆ haloalkyl groups and halogen atoms;

(13) R² is as defined in any one of (10) to (12) above in which thesubstituent is at the meta position;

(14) Compounds in which R³ represents a hydrogen atom;

(15) Compounds in which R⁴ represents a substituted phenyl group havingfrom 1 to 3 C₁ -C₆ alkoxy substituents, more especially from 1 to 3 C₁-C₃ alkoxy substituents and most especially from 1 to 3 methoxysubstituents;

(16) Compounds in which B' represents a carbonyl group.

Most preferred are those compounds in which R¹ is as defined in (7) or(8) above, R² is as defined in any one of (9) to (13) above, R³ is asdefined in (14) above, R⁴ is as defined in (15) above, B is as definedin (16) above, X is as defined in (5) above and A is as defined in (6)above. defined in (6) above.

Examples of specific compounds of the invention are given in thefollowing formulae (I-1) to (I-3), in which the substituents are asdefined in the corresponding one of Tables 1 to 3 [i.e. Table 1 relatesto formula (I-1), Table 2 relates to formula (I-2) and so on]. In theTables, the following abbreviations are used:

    ______________________________________                                               Bu         butyl                                                              iBu        isobutyl                                                           sBu        sec-butyl                                                          Et         ethyl                                                              Hx         hexyl                                                              Me         methyl                                                             Np         naphthyl                                                           Ph         phenyl                                                             Pn         pentyl                                                             Pr         propyl                                                             Pyr        pyridyl                                                            Quin       quinolyl                                                           Tfm        trifluoromethyl                                                    Thi        thienyl                                                     ______________________________________                                         ##STR3##                                                                      (I1)                                                                          ##STR4##                                                                      (I2)                                                                          ##STR5##                                                                      (I3)                                                                     

                  TABLE 1                                                         ______________________________________                                        Compound                                                                      No.     R.sup.1        R.sup.2      B'                                        ______________________________________                                        1-1     Ph             Ph           C═O                                   1-2     4-MeOPh        4-MeOPh      C═O                                   1-3     4-ClPh         4-ClPh       C═O                                   1-4     2-Thi          2-Thi        C═O                                   1-5     4-Pyr          4-Pyr        C═O                                   1-6     2-Np           2-Np         C═O                                   1-7     1-Np           1-Np         C═O                                   1-8     3-Pyr          3-Pyr        C═O                                   1-9     2-Pyr          2-Pyr        C═O                                   1-10    2-Quin         2-Quin       C═O                                   1-11    PhC.tbd.C--    PhC.tbd.C--  C═O                                   1-12    PhCH═CH--  PhCH═CH--                                                                              C═O                                   1-13    3-Thi          3-Thi        C═O                                   1-14    3,4-diMeOPh    3,4-diMeOPh  C═O                                   1-15    3,4,5-TriMeOPh 3,4,5-TriMeOPh                                                                             C═O                                   1-16    Ph             4-MeOPh      C═O                                   1-17    Ph             4-ClPh       C═O                                   1-18    Ph             2-Thi        C═O                                   1-19    Ph             4-Pyr        C═O                                   1-20    Ph             2-Np         C═O                                   1-21    Ph             1-Np         C═O                                   1-22    Ph             3-Pyr        C═O                                   1-23    Ph             2-Pyr        C═O                                   1-24    Ph             2-Quin       C═O                                   1-25    Ph             PhC.tbd.C--  C═O                                   1-26    Ph             PhCH═CH--                                                                              C═O                                   1-27    Ph             3-Thi        C═O                                   1-28    Ph             3,4-diMeOPh  C═O                                   1-29    Ph             3,4,5-TriMeOPh                                                                             C═O                                   1-30    4-MeOPh        4-ClPh       C═O                                   1-31    4-MeOPh        2-Thi        C═O                                   1-32    3-MeOPh        4-Pyr        C═O                                   1-33    4-MeOPh        2-Np         C═O                                   1-34    4-MeOPh        1-Np         C═O                                   1-35    4-MeOPh        3-Pyr        C═O                                   1-36    4-MeOPh        2-Pyr        C═O                                   1-37    4-MeOPh        2-Quin       C═O                                   1-38    4-MeOPh        PhC.tbd.C--  C═O                                   1-39    4-MeOPh        PhCH═CH--                                                                              C═O                                   1-40    4-MeOPh        3-Thi        C═O                                   1-41    4-MeOPh        3,4-diMeOPh  C═O                                   1-42    4-MeOPh        3,4,5-TriMeOPh                                                                             C═O                                   1-43    4-ClPh         2-Thi        C═O                                   1-44    4-ClPh         4-Pyr        C═O                                   1-45    4-ClPh         2-Np         C═O                                   1-46    4-ClPh         1-Np         C═O                                   1-47    2-ClPh         3-Pyr        C═O                                   1-48    3-ClPh         2-Pyr        C═O                                   1-49    4-ClPh         2-Quin       C═O                                   1-50    4-ClPh         PhC.tbd.C--  C═O                                   1-51    4-ClPh         PhCH═CH--                                                                              C═O                                   1-52    4-ClPh         3-Thi        C═O                                   1-53    4-ClPh         3,4-diMeOPh  C═O                                   1-54    4-ClPh         3,4,5-TriMeOPh                                                                             C═O                                   1-55    2-Thi          4-Pyr        C═O                                   1-56    2-Thi          2-Np         C═O                                   1-57    2-Thi          1-Np         C═O                                   1-58    2-Thi          3-Pyr        C═O                                   1-59    2-Thi          2-Pyr        C═O                                   1-60    2-Thi          2-Quin       C═O                                   1-61    2-Thi          PhC.tbd.C--  C═O                                   1-62    2-Thi          PhCH═CH--                                                                              C═O                                   1-63    2-Thi          3-Thi        C═O                                   1-64    2-Thi          3,4-diMeOPh  C═O                                   1-65    2-Thi          3,4,5-TriMeOPh                                                                             C═O                                   1-66    4-Pyr          2-Np         C═O                                   1-67    4-Pyr          1-Np         C═O                                   1-68    4-Pyr          3-Pyr        C═O                                   1-69    4-Pyr          2-Pyr        C═O                                   1-70    4-Pyr          2-Quin       C═O                                   1-71    4-Pyr          PhC.tbd.C--  C═O                                   1-72    4-Pyr          PhCH═CH--                                                                              C═O                                   1-73    4-Pyr          3-Thi        C═O                                   1-74    4-Pyr          3,4-diMeOPh  C═O                                   1-75    4-Pyr          3,4,5-TriMeOPh                                                                             C═O                                   1-76    2-Np           1-Np         C═O                                   1-77    2-Np           3-Pyr        C═O                                   1-78    2-Np           2-Pyr        C═O                                   1-79    2-Np           2-Quin       C═O                                   1-80    2-Np           PhC.tbd.C--  C═O                                   1-81    2-Np           PhCH═CH--                                                                              C═O                                   1-82    2-Np           3-Thi        C═O                                   1-83    2-Np           3,4-diMeOPh  C═O                                   1-84    2-Np           3,4,5-TriMeOPh                                                                             C═O                                   1-85    1-Np           3-Pyr        C═O                                   1-86    1-Np           2-Pyr        C═O                                   1-87    1-Np           2-Quin       C═O                                   1-88    1-Np           PhC.tbd.C--  C═O                                   1-89    1-Np           PhCH═CH--                                                                              C═O                                   1-90    1-Np           3-Thi        C═O                                   1-91    1-Np           3,4-diMeOPh  C═O                                   1-92    1-Np           3,4,5-TriMeOPh                                                                             C═O                                   1-93    3-Pyr          2-Pyr        C═O                                   1-94    3-Pyr          2-Quin       C═O                                   1-95    3-Pyr          PhC.tbd.C--  C═O                                   1-96    3-Pyr          PhCH═CH--                                                                              C═O                                   1-97    3-Pyr          3-Thi        C═O                                   1-98    3-Pyr          3,4-diMeOPh  C═O                                   1-99    3-Pyr          3,4,5-TriMeOPh                                                                             C═O                                   1-100   2-Pyr          2-Quin       C═O                                   1-101   3-Pyr          PhC.tbd.C--  C═O                                   1-102   2-Pyr          PhCH═CH--                                                                              C═O                                   1-103   3-Pyr          3-Thi        C═O                                   1-104   2-Quin         PhC.tbd.C--  C═O                                   1-105   2-Quin         PhCH═CH--                                                                              C═O                                   1-106   2-Quin         3-Thi        C═O                                   1-107   2-Quin         3,4-diMeOPh  C═O                                   1-108   2-Quin         3,4,5-TriMeOPh                                                                             C═O                                   1-109   PhC.tbd.C--    PhCH═CH--                                                                              C═O                                   1-110   PhC.tbd.C--    3-Thi        C═O                                   1-111   PhC.tbd.C--    3,4-diMeOPh  C═O                                   1-112   PhC.tbd.C--    3,4,5-TriMeOPh                                                                             C═O                                   1-113   PhCH═CH--  3-Thi        C═O                                   1-114   PhCH═CH--  3,4-diMeOPh  C═O                                   1-115   PhCH═CH--  3,4,5-TriMeOPh                                                                             C═O                                   1-116   Ph             Ph           C═S                                   1-117   4-MeOPh        4-MeOPh      C═S                                   1-118   4-ClPh         4-ClPh       C═S                                   1-119   2-Thi          2-Thi        C═S                                   1-120   4-FPh          4-FPh        C═S                                   1-121   2-Np           2-Np         C═S                                   1-122   1-Np           1-Np         C═S                                   1-123   3-Pyr          3-Pyr        C═S                                   1-124   2-Pyr          2-Pyr        C═S                                   1-125   2-Quin         2-Quin       C═S                                   1-126   PhC.tbd.C--    PhC.tbd.C--  C═S                                   1-127   PhCH═CH--  PhCH═CH--                                                                              C═S                                   1-128   3-Thi          3-Thi        C═S                                   1-129   Ph             4-MeOPh      C═S                                   1-130   Ph             4-ClPh       C═S                                   1-131   Ph             2-Thi        C═S                                   1-132   Ph             4-Pyr        C═S                                   1-133   Ph             2-Np         C═S                                   1-134   Ph             1-Np         C═S                                   1-135   Ph             3-Pyr        C═S                                   1-136   Ph             2-Pyr        C═S                                   1-137   Ph             2-Quin       C═S                                   1-138   Ph             PhC.tbd.C--  C═S                                   1-139   Ph             PhCH═CH--                                                                              C═S                                   1-140   Ph             3-Thi        C═S                                   1-141   4-MeOPh        4-ClPh       C═S                                   1-142   2-MeOPh        2-Thi        C═S                                   1-143   3-MeOPh        4-Pyr        C═S                                   1-144   4-MeOPh        2-Np         C═S                                   1-145   4-MeOPh        1-Np         C═S                                   1-146   4-MeOPh        3-Pyr        C═S                                   1-147   4-MeOPh        2-Pyr        C═S                                   1-148   4-MeOPh        2-Quin       C═S                                   1-149   4-MeOPh        PhC.tbd.C--  C═S                                   1-150   4-MeOPh        PhCH═CH--                                                                              C═S                                   1-151   4-MeOPh        3-Thi        C═S                                   1-152   4-ClPh         2-Thi        C═S                                   1-153   4-ClPh         4-Pyr        C═S                                   1-154   3-ClPh         2-Np         C═S                                   1-155   3-ClPh         1-Np         C═S                                   1-156   2-ClPh         3-Pyr        C═S                                   1-157   3-ClPh         2-Pyr        C═S                                   1-158   4-ClPh         2-Quin       C═S                                   1-159   4-ClPh         PhC.tbd.C--  C═S                                   1-160   4-ClPh         PhCH═CH--                                                                              C═S                                   1-161   4-ClPh         3-Thi        C═S                                   1-162   2-Thi          4-Pyr        C═S                                   1-163   2-Thi          2-Np         C═S                                   1-164   2-Thi          1-Np         C═S                                   1-165   2-Thi          3-Pyr        C═S                                   1-166   2-Thi          2-Pyr        C═S                                   1-167   2-Thi          2-Quin       C═S                                   1-168   2-Thi          PhC.tbd.C--  C═S                                   1-169   2-Thi          PhCH═CH--                                                                              C═S                                   1-170   2-Thi          3-Thi        C═S                                   1-171   4-Pyr          2-Np         C═S                                   1-172   4-Pyr          1-Np         C═S                                   1-173   4-Pyr          3-Pyr        C═S                                   1-174   4-Pyr          2-Pyr        C═S                                   1-175   4-Pyr          2-Quin       C═S                                   1-176   4-Pyr          PhC.tbd.C--  C═S                                   1-177   4-Pyr          PhCH═CH--                                                                              C═S                                   1-178   4-Pyr          3-Thi        C═S                                   1-179   2-Np           1-Np         C═S                                   1-180   2-Np           3-Pyr        C═S                                   1-181   2-Np           2-Pyr        C═S                                   1-182   2-Np           2-Quin       C═S                                   1-183   2-Np           PhC.tbd.C--  C═S                                   1-184   2-Np           PhCH═CH--                                                                              C═S                                   1-185   2-Np           3-Thi        C═S                                   1-186   1-Np           3-Pyr        C═S                                   1-187   1-Np           2-Pyr        C═S                                   1-188   1-Np           2-Quin       C═S                                   1-189   1-Np           PhC.tbd.C--  C═S                                   1-190   1-Np           PhCH═CH--                                                                              C═S                                   1-191   1-Np           3-Thi        C═S                                   1-192   3-Pyr          2-Pyr        C═S                                   1-193   3-Pyr          2-Quin       C═S                                   1-194   3-Pyr          PhC.tbd.C--  C═S                                   1-195   3-Pyr          PhCH═CH--                                                                              C═S                                   1-196   3-Pyr          3-Thi        C═S                                   1-197   2-Pyr          2-Quin       C═S                                   1-198   3-Pyr          PhC.tbd.C--  C═S                                   1-199   2-Pyr          PhCH═CH--                                                                              C═S                                   1-200   3-Pyr          3-Thi        C═S                                   1-201   2-Quin         PhC.tbd.C--  C═S                                   1-202   2-Quin         PhCH═CH--                                                                              C═S                                   1-203   2-Quin         3-Thi        C═S                                   1-204   PhC.tbd.C--    PhCH═CH--                                                                              C═S                                   1-205   PhC.tbd.C--    3-Thi        C═S                                   1-206   PhCH═CH--  3-Thi        C═S                                   1-207   Ph             Ph           SO.sub.2                                  1-208   4-MeOPh        4-MeOPh      SO.sub.2                                  1-209   4-ClPh         4-ClPh       SO.sub.2                                  1-210   2-Thi          2-Thi        SO.sub.2                                  1-211   4-Pyr          4-Pyr        SO.sub.2                                  1-212   2-Np           2-Np         SO.sub.2                                  1-213   1-Np           1-Np         SO.sub.2                                  1-214   3-Pyr          3-Pyr        SO.sub.2                                  1-215   2-Pyr          2-Pyr        SO                                        1-216   2-Quin         2-Quin       SO.sub.2                                  1-217   PhC.tbd.C--    PhC.tbd.C--  SO.sub.2                                  1-218   PhCH═CH--  PhCH═CH--                                                                              SO.sub.2                                  1-219   3-Thi          3-Thi        SO.sub.2                                  1-220   Ph             4-MeOPh      SO.sub.2                                  1-221   Ph             4-ClPh       SO.sub.2                                  1-222   Ph             2-Thi        SO.sub.2                                  1-223   Ph             4-Pyr        SO.sub.2                                  1-224   Ph             2-Np         SO.sub.2                                  1-225   Ph             1-Np         SO.sub.2                                  1-226   Ph             3-Pyr        SO.sub.2                                  1-227   Ph             2-Pyr        SO.sub.2                                  1-228   Ph             2-Quin       SO.sub.2                                  1-229   Ph             PhC.tbd.C--  SO.sub.2                                  1-230   Ph             PhCH═CH--                                                                              SO.sub.2                                  1-231   Ph             3-Thi        SO.sub.2                                  1-232   4-MeOPh        4-ClPh       SO.sub.2                                  1-233   2-MeOPh        2-Thi        SO.sub.2                                  1-234   3-MeOPh        4-Pyr        SO.sub.2                                  1-235   4-MeOPh        2-Np         SO.sub.2                                  1-236   4-MeOPh        1-Np         SO.sub.2                                  1-237   4-MeOPh        3-Pyr        SO                                        1-238   4-MeOPh        2-Pyr        SO.sub.2                                  1-239   4-MeOPh        2-Quin       SO.sub.2                                  1-240   4-MeOPh        PhC.tbd.C--  SO.sub.2                                  1-241   4-MeOPh        PhCH═CH--                                                                              SO.sub.2                                  1-242   4-MeOPh        3-Thi        SO.sub.2                                  1-243   4-ClPh         2-Thi        SO.sub.2                                  1-244   4-ClPh         4-Pyr        SO.sub.2                                  1-245   4-ClPh         2-Np         SO.sub.2                                  1-246   4-ClPh         1-Np         SO                                        1-247   2-ClPh         3-Pyr        SO.sub.2                                  1-248   3-ClPh         2-Pyr        SO.sub.2                                  1-249   4-ClPh         2-Quin       SO.sub.2                                  1-250   4-ClPh         PhC.tbd.C--  SO.sub.2                                  1-251   4-ClPh         PhCH═CH--                                                                              SO.sub.2                                  1-252   4-ClPh         3-Thi        SO.sub.2                                  1-253   2-Thi          4-Pyr        SO.sub.2                                  1-254   2-Thi          2-Np         SO.sub.2                                  1-255   2-Thi          1-Np         SO.sub.2                                  1-256   2-Thi          3-Pyr        SO                                        1-257   2-Thi          2-Pyr        SO.sub.2                                  1-258   2-Thi          2-Quin       SO.sub.2                                  1-259   2-Thi          PhC.tbd.C--  SO.sub.2                                  1-260   2-Thi          PhCH═CH--                                                                              SO.sub.2                                  1-261   2-Thi          3-Thi        SO.sub.2                                  1-262   4-Pyr          2-Np         SO.sub.2                                  1-263   4-Pyr          1-Np         SO.sub.2                                  1-264   4-Pyr          3-Pyr        SO.sub.2                                  1-265   4-Pyr          2-Pyr        SO.sub.2                                  1-266   4-Pyr          2-Quin       SO.sub.2                                  1-267   4-Pyr          PhC.tbd.C--  SO.sub.2                                  1-268   4-Pyr          PhCH═CH--                                                                              SO                                        1-269   4-Pyr          3-Thi        SO.sub.2                                  1-270   2-Np           1-Np         SO.sub.2                                  1-271   2-Np           3-Pyr        SO.sub.2                                  1-272   2-Np           2-Pyr        SO.sub.2                                  1-273   2-Np           2-Quin       SO.sub.2                                  1-274   2-Np           PhC.tbd.C--  SO.sub.2                                  1-275   2-Np           PhCH═CH--                                                                              SO.sub.2                                  1-276   2-Np           3-Thi        SO.sub.2                                  1-277   1-Np           3-Pyr        SO.sub.2                                  1-278   1-Np           2-Pyr        SO.sub.2                                  1-279   1-Np           2-Quin       SO.sub.2                                  1-280   1-Np           PhC.tbd.C--  SO.sub.2                                  1-281   1-Np           PhCH═CH--                                                                              SO                                        1-282   1-Np           3-Thi        SO.sub.2                                  1-283   3-Pyr          2-Pyr        SO.sub.2                                  1-284   3-Pyr          2-Quin       SO.sub.2                                  1-285   3-Pyr          PhC.tbd.C--  SO.sub.2                                  1-286   3-Pyr          PhCH═CH--                                                                              SO.sub.2                                  1-287   3-Pyr          3-Thi        SO.sub.2                                  1-288   2-Pyr          2-Quin       SO.sub.2                                  1-289   3-Pyr          PhC.tbd.C--  SO.sub.2                                  1-290   2-Pyr          PhCH═CH--                                                                              SO.sub.2                                  1-291   3-Pyr          3-Thi        SO.sub.2                                  1-292   2-Quin         PhC.tbd.C--  SO.sub.2                                  1-293   2-Quin         PhCH═CH--                                                                              SO.sub.2                                  1-294   2-Quin         3-Thi        SO.sub.2                                  1-295   PhC.tbd.C--    PhCH═CH--                                                                              SO.sub.2                                  1-296   PhC.tbd.C--    3-Thi        SO.sub.2                                  1-297   PhCH═CH--  3-Thi        SO.sub.2                                  1-298   Ph             Ph           CH.sub.2                                  1-299   4-MeOPh        4-MeOPh      CH.sub.2                                  1-300   4-ClPh         4-ClPh       CH.sub.2                                  1-301   2-Thi          2-Thi        CH.sub.2                                  1-302   4-Pyr          4-Pyr        CH.sub.2                                  1-303   2-Np           2-Np         CH.sub.2                                  1-304   1-Np           1-Np         CH.sub.2                                  1-305   3-Pyr          3-Pyr        CH.sub.2                                  1-306   2-Pyr          2-Pyr        CH.sub.2                                  1-307   2-Quin         2-Quin       CH.sub.2                                  1-308   PhC.tbd.C--    PhC.tbd.C--  CH.sub.2                                  1-309   PhCH═CH--  PhCH═CH--                                                                              CH.sub.2                                  1-310   3-Thi          3-Thi        CH.sub.2                                  1-311   3,4-diMeOPh    3,4-diMeOPh  CH.sub.2                                  1-312   3,4,5-TriMeOPh 3,4,5-TriMeOPh                                                                             CH.sub.2                                  1-313   Ph             4-MeOPh      CH.sub.2                                  1-314   Ph             4-ClPh       CH.sub.2                                  1-315   Ph             2-Thi        CH.sub.2                                  1-316   Ph             4-Pyr        CH.sub.2                                  1-317   Ph             2-Np         CH.sub.2                                  1-318   Ph             1-Np         CH.sub.2                                  1-319   Ph             3-Pyr        CH.sub.2                                  1-320   Ph             2-Pyr        CH.sub.2                                  1-321   Ph             2-Quin       CH.sub.2                                  1-322   Ph             PhC.tbd.C--  CH.sub.2                                  1-323   Ph             PhCH═CH--                                                                              CH.sub.2                                  1-324   Ph             3-Thi        CH.sub.2                                  1-325   Ph             3,4-diMeOPh  CH.sub.2                                  1-326   Ph             3,4,5-TriMeOPh                                                                             CH.sub.2                                  1-327   4-MeOPh        4-ClPh       CH.sub.2                                  1-328   2-MeOPh        2-Thi        CH.sub.2                                  1-329   3-MeOPh        4-Pyr        CH.sub.2                                  1-330   4-MeOPh        2-Np         CH.sub.2                                  1-331   4-MeOPh        1-Np         CH.sub.2                                  1-332   4-MeOPh        3-Pyr        CH.sub.2                                  1-333   4-MeOPh        2-Pyr        CH.sub.2                                  1-334   4-MeOPh        2-Quin       CH.sub.2                                  1-335   4-MeOPh        PhC.tbd.C--  CH.sub.2                                  1-336   4-MeOPh        PhCH═CH--                                                                              CH.sub.2                                  1-337   4-MeOPh        3-Thi        CH.sub.2                                  1-338   4-MeOPh        3,4-diMeOPh  CH.sub.2                                  1-339   4-MeOPh        3,4,5-TriMeOPh                                                                             CH.sub.2                                  1-340   4-ClPh         2-Thi        CH.sub.2                                  1-341   4-ClPh         4-Pyr        CH.sub.2                                  1-342   3-ClPh         2-Np         CH.sub.2                                  1-343   3-ClPh         1-Np         CH.sub.2                                  1-344   2-ClPh         3-Pyr        CH.sub.2                                  1-345   3-ClPh         2-Pyr        CH.sub.2                                  1-346   4-ClPh         2-Quin       CH.sub.2                                  1-347   4-ClPh         PhC.tbd.C--  CH.sub.2                                  1-348   4-ClPh         PhCH═CH--                                                                              CH.sub.2                                  1-349   4-ClPh         3-Thi        CH.sub.2                                  1-350   4-ClPh         3,4-diMeOPh  CH.sub.2                                  1-351   4-ClPh         3,4,5-TriMeOPh                                                                             CH.sub.2                                  1-352   2-Thi          4-Pyr        CH.sub.2                                  1-353   2-Thi          2-Np         CH.sub.2                                  1-354   2-Thi          1-Np         CH.sub.2                                  1-355   2-Thi          3-Pyr        CH.sub.2                                  1-356   2-Thi          2-Pyr        CH.sub.2                                  1-357   2-Thi          2-Quin       CH.sub.2                                  1-358   2-Thi          PhC.tbd.C--  CH.sub.2                                  1-359   2-Thi          PhCH═CH--                                                                              CH.sub.2                                  1-360   2-Thi          3-Thi        CH.sub.2                                  1-361   2-Thi          3,4-diMeOPh  CH.sub.2                                  1-362   2-Thi          3,4,5-TriMeOPh                                                                             CH.sub.2                                  1-363   4-Pyr          2-Np         CH.sub.2                                  1-364   4-Pyr          1-Np         CH.sub.2                                  1-365   4-Pyr          3-Pyr        CH.sub.2                                  1-366   4-Pyr          2-Pyr        CH.sub.2                                  1-367   4-Pyr          2-Quin       CH.sub.2                                  1-368   4-Pyr          PhC.tbd.C--  CH.sub.2                                  1-369   4-Pyr          PhCH═CH--                                                                              CH.sub.2                                  1-370   4-Pyr          3-Thi        CH.sub.2                                  1-371   4-Pyr          3,4-diMeOPh  CH.sub.2                                  1-372   4-Pyr          3,4,5-TriMeOPh                                                                             CH.sub.2                                  1-373   2-Np           1-Np         CH.sub.2                                  1-374   2-Np           3-Pyr        CH.sub.2                                  1-375   2-Np           2-Pyr        CH.sub.2                                  1-376   2-Np           2-Quin       CH.sub.2                                  1-377   2-Np           PhC.tbd.C--  CH.sub.2                                  1-378   2-Np           PhCH═CH--                                                                              CH.sub.2                                  1-379   2-Np           3-Thi        CH.sub.2                                  1-380   2-Np           3,4-diMeOPh  CH.sub.2                                  1-381   2-Np           3,4,5-TriMeOPh                                                                             CH.sub.2                                  1-382   1-Np           3-Pyr        CH.sub.2                                  1-383   1-Np           2-Pyr        CH.sub.2                                  1-384   1-Np           2-Quin       CH.sub.2                                  1-385   1-Np           PhC.tbd.C--  CH.sub.2                                  1-386   1-Np           PhCH═CH--                                                                              CH.sub.2                                  1-387   1-Np           3-Thi        CH.sub.2                                  1-388   1-Np           3,4-diMeOPh  CH.sub.2                                  1-389   1-Np           3,4,5-TriMeOPh                                                                             CH.sub.2                                  1-390   3-Pyr          2-Pyr        CH.sub.2                                  1-391   3-Pyr          2-Quin       CH.sub.2                                  1-392   3-Pyr          PhC.tbd.C--  CH.sub.2                                  1-393   3-Pyr          PhCH═CH--                                                                              CH.sub.2                                  1-394   3-Pyr          3-Thi        CH.sub.2                                  1-395   3-Pyr          3,4-diMeOPh  CH.sub.2                                  1-396   3-Pyr          3,4,5-TriMeOPh                                                                             CH.sub.2                                  1-397   2-Pyr          2-Quin       CH.sub.2                                  1-398   3-Pyr          PhC.tbd.C--  CH.sub.2                                  1-399   2-Pyr          PhCH═CH--                                                                              CH.sub.2                                  1-400   3-Pyr          3-Thi        CH.sub.2                                  1-401   2-Quin         PhC.tbd.C--  CH.sub.2                                  1-402   2-Quin         PhCH═CH--                                                                              CH.sub.2                                  1-403   2-Quin         3-Thi        CH.sub.2                                  1-404   2-Quin         3,4-diMeOPh  CH.sub.2                                  1-405   2-Quin         3,4,5-TriMeOPh                                                                             CH.sub.2                                  1-406   PhC.tbd.C--    PhCH═CH--                                                                              CH.sub.2                                  1-407   PhC.tbd.C--    3-Thi        CH.sub.2                                  1-408   PhC.tbd.C--    3,4-diMeOPh  CH.sub.2                                  1-409   PhC.tbd.C--    3,4,5-TriMeOPh                                                                             CH.sub.2                                  1-410   PhCH═CH--  3-Thi        CH.sub.2                                  1-411   3-MeOPh        3-MeOPh      C═O                                   1-412   3-MeOPh        4-MeOPh      C═O                                   1-413   2-MeOPh        2-MeOPh      C═O                                   1-414   2-MeOPh        3-MeOPh      C═O                                   1-415   2-MeOPh        4-MeOPh      C═O                                   1-416   2-ClPh         2-ClPh       C═O                                   1-417   2-ClPh         3-ClPh       C═O                                   1-418   2-ClPh         4-ClPh       C═O                                   1-419   3-ClPh         3-ClPh       C═O                                   1-420   3-ClPh         4-ClPh       C═O                                   1-421   2-MePh         2-MePh       C═O                                   1-422   2-MePh         3-MePh       C═O                                   1-423   2-MePh         4-MePh       C═O                                   1-424   3-MePh         3-MePh       C═O                                   1-425   3-MePh         4-MePh       C═O                                   1-426   3-TfmPh        3-TfmPh      C═O                                   1-427   3-TfmCH.sub.2 Ph                                                                             3-TfmCH.sub.2 Ph                                                                           C═O                                   1-428   2-PrOPh        2-PrOPh      C═O                                   1-429   2-PrOPh        3-PrOPh      C═O                                   1-430   2-PrOPh        4-PrOPh      C═O                                   1-431   3-PrOPh        3-PrOPh      C═O                                   1-432   3-PrOPh        4-PrOPh      C═O                                   1-433   4-PrOPh        4-PrOPh      C═O                                   1-434   3- sBuOPh      3- sBuOPh    C═O                                   1-435   4- sBuOPh      4- sBuOPh    C═O                                   1-436   3- iBuOPh      3- iBuOPh    C═O                                   1-437   4- iBuOPh      4- iBuOPh    C═O                                   1-438   2-EtPh         2-EtPh       C═O                                   1-439   2-EtPh         3-EtPh       C═O                                   1-440   2-EtPh         4-EtPh       C═O                                   1-441   3-EtPh         3-EtPh       C═O                                   1-442   3-EtPh         4-EtPh       C═O                                   1-443   4-EtPh         4-EtPh       C═O                                   1-444   2-PrPh         2-PrPh       C═O                                   1-445   2-PrPh         3-PrPh       C═O                                   1-446   2-PrPh         4-PrPh       C═O                                   1-447   3-PrPh         3-PrPh       C═O                                   1-448   3-PrPh         4-PrPh       C═O                                   1-449   4-PrPh         4-PrPh       C═O                                   1-450   3- iBuPh       3- iBuPh     C═O                                   1-451   3- iBuPh       4- iBuPh     C═O                                   1-452   2-ClPh         Ph           C═O                                   1-453   2-ClPh         3-MeOPh      C═O                                   1-454   2-ClPh         4-MeOPh      C═O                                   1-455   2-ClPh         3-PrOPh      C═O                                   1-456   2-ClPh         4-PrOPh      C═O                                   1-457   2-ClPh         3-BuOPh      C═O                                   1-458   2-ClPh         4-BuOPh      C═O                                   1-459   2-ClPh         3-MePh       C═O                                   1-460   2-ClPh         4-MePh       C═O                                   1-461   2-ClPh         3-TfmPh      C═O                                   1-462   2-ClPh         3,4-diMeOPh  C═O                                   1-463   2-ClPh         3-MeO-4-PrOPh                                                                              C═O                                   1-464   2-ClPh         3,4-diPrOPh  C═O                                   1-465   2-ClPh         3,4-diClPh   C═O                                   1-466   3-ClPh         Ph           C═O                                   1-467   3-ClPh         3-MeOPh      C═O                                   1-468   3-ClPh         4-MeOPh      C═O                                   1-469   3-ClPh         3-PrOPh      C═O                                   1-470   3-ClPh         4-PrOPh      C═O                                   1-471   3-ClPh         3- iBuOPh    C═O                                   1-472   3-ClPh         4- iBuOPh    C═O                                   1-473   3-ClPh         2-MePh       C═O                                   1-474   3-ClPh         3-MePh       C═O                                   1-475   3-ClPh         4-MePh       C═O                                   1-476   3-ClPh         3-TfmPh      C═O                                   1-477   3-ClPh         3-EtPh       C═O                                   1-478   3-ClPh         4-EtPh       C═O                                   1-479   3-ClPh         3-PrPh       C═O                                   1-480   3-ClPh         4-PrPh       C═O                                   1-481   3-ClPh         2,3-diMeOPh  C═O                                   1-482   3-ClPh         3,4-diMeOPh  C═O                                   1-483   3-ClPh         4-MeO-3-PrOPh                                                                              C═O                                   1-484   3-ClPh         3,4-diPrOPh  C═O                                   1-485   3-ClPh         2,3-diClPh   C═O                                   1-486   3-ClPh         3,4-diClPh   C═O                                   1-487   4-ClPh         3-MeOPh      C═O                                   1-488   4-ClPh         4-MeOPh      C═O                                   1-489   4-ClPh         3-PrOPh      C═O                                   1-490   4-ClPh         4-PrOPh      C═O                                   1-491   4-ClPh         3- iBuOPh    C═O                                   1-492   4-ClPh         4- iBuOPh    C═O                                   1-493   4-ClPh         2,3-diClPh   C═O                                   1-494   2,3-diClPh     Ph           C═O                                   1-495   2,3-diClPh     3-MeOPh      C═O                                   1-496   2,3-diClPh     4-MeOPh      C═O                                   1-497   2,3-diClPh     3-PrOPh      C═O                                   1-498   2,3-diClPh     4-PrOPh      C═O                                   1-499   2,3-diClPh     3- sBuOPh    C═O                                   1-500   2,3-diClPh     4- sBuOPh    C═O                                   1-501   2,3-diClPh     3,4-diMeOPh  C═O                                   1-502   2,3-diClPh     3-MePh       C═O                                   1-503   2,3-diClPh     4-MePh       C═O                                   1-504   2,3-diClPh     3-EtPh       C═O                                   1-505   2,3-diClPh     4-EtPh       C═O                                   1-506   2,3-diClPh     3-PrPh       C═O                                   1-507   2,3-diClPh     4-PrPh       C═O                                   1-508   2,3-diClPh     3- iBuOPh    C═O                                   1-509   2,3-diClPh     4- iBuOPh    C═O                                   1-510   3,4-diClPh     Ph           C═O                                   1-511   3,4-diClPh     2-MeOPh      C═O                                   1-512   3,4-diClPh     3-MeOPh      C═O                                   1-513   3,4-diClPh     4-MeOPh      C═O                                   1-514   3,4-diClPh     3-PrOPh      C═O                                   1-515   3,4-diClPh     4-PrOPh      C═O                                   1-516   3,4-diClPh     3- iBuOPh    C═O                                   1-517   3,4-diClPh     4- iBuOPh    C═O                                   1-518   3,4-diClPh     3-MePh       C═O                                   1-519   3,4-diClPh     4-MePh       C═O                                   1-520   3,4-diClPh     3-PrPh       C═O                                   1-521   3,4-diClPh     4-PrPh       C═O                                   1-522   3,4-diClPh     3- iBuPh     C═O                                   1-523   3,4-diClPh     4- iBuPh     C═O                                   1-524   3-FPh          3-FPh        C═O                                   1-525   4-FPh          4-FPh        C═O                                   1-526   4-FPh          Ph           C═O                                   1-527   3-FPh          4-FPh        C═O                                   1-528   3-FPh          3-MeOPh      C═O                                   1-529   3-FPh          4-MeOPh      C═O                                   1-530   3-FPh          3-PrOPh      C═O                                   1-531   3-FPh          4-PrOPh      C═O                                   1-532   3-FPh          3- iBuOPh    C═O                                   1-533   3-FPh          4- iBuOPh    C═O                                   1-534   3-FPh          3-MePh       C═O                                   1-535   3-FPh          4-MePh       C═O                                   1-536   3-FPh          3,4-diMePh   C═O                                   1-537   3-FPh          3-TfmPh      C═O                                   1-538   3-FPh          3-EtPh       C═O                                   1-539   3-FPh          4-PrPh       C═O                                   1-540   3-FPh          4- iBuPh     C═O                                   1-541   3-FPh          3,4-diMeOPh  C═O                                   1-542   3-FPh          2-ClPh       C═O                                   1-543   3-FPh          3-ClPh       C═O                                   1-544   3-FPh          4-ClPh       C═O                                   1-545   3-FPh          2,3-diClPh   C═O                                   1-546   3-FPh          3,4-diClPh   C═O                                   1-547   3-FPh          4-PrPh       C═O                                   1-548   3-FPh          4- iBuPh     C═O                                   1-549   4-FPh          Ph           C═O                                   1-550   4-FPh          3,4-diClPh   C═O                                   1-551   4-FPh          3,4-diMeOPh  C═O                                   1-552   4-FPh          3,4,5-triMeOPh                                                                             C═O                                   1-553   4-FPh          3-MePh       C═O                                   1-554   4-FPh          4-MePh       C═O                                   1-555   4-FPh          3,4-diMePh   C═O                                   1-556   3-TfmPh        Ph           C═O                                   1-557   3-TfmPh        3-MeOPh      C═O                                   1-558   3-TfmPh        4-MeOPh      C═O                                   1-559   3-TfmPh        3-PrOPh      C═O                                   1-560   3-TfmPh        4-PrOPh      C═O                                   1-561   3-TfmPh        3- iBuOPh    C═O                                   1-562   3-TfmPh        4- iBuOPh    C═O                                   1-563   3-TfmPh        3-MePh       C═O                                   1-564   3-TfmPh        4-MePh       C═O                                   1-565   3-TfmPh        2,3-diMePh   C═O                                   1-566   3-TfmPh        3,4-diMePh   C═O                                   1-567   3-TfmPh        3-EtPh       C═O                                   1-568   3-TfmPh        4-EtPh       C═O                                   1-569   3-TfmPh        3-PrPh       C═O                                   1-570   3-TfmPh        4-PrPh       C═O                                   1-571   3-TfmPh        3- iBuPh     C═O                                   1-572   3-TfmPh        4- iBuPh     C═O                                   1-573   3-TfmPh        2,3-diMeOPh  C═O                                   1-574   3-TfmPh        3,4-diMeOPh  C═O                                   1-575   2-MePh         Ph           C═O                                   1-576   2-MePh         3,4-diMePh   C═O                                   1-577   2-MePh         3,4-diMeOPh  C═O                                   1-578   2-MePh         3-PrPh       C═O                                   1-579   2-MePh         4- iBuPh     C═O                                   1-580   3-MePh         Ph           C═O                                   1-581   3-MePh         1-Np         C═O                                   1-582   3-MePh         2-Np         C═O                                   1-583   3-MePh         3,4-diMePh   C═O                                   1-584   3-MePh         3-EtPh       C═O                                   1-585   3-MePh         4-EtPh       C═O                                   1-586   3-MePh         3-PrPh       C═O                                   1-587   3-MePh         4-PrPh       C═O                                   1-588   3-MePh         3- iBuPh     C═O                                   1-589   3-MePh         4- iBuPh     C═O                                   1-590   3-MePh         3,4-diMeOPh  C═O                                   1-591   3-MePh         3-MeOPh      C═O                                   1-592   3-MePh         4-MeOPh      C═O                                   1-593   3-MePh         3-PrOPh      C═O                                   1-594   3-MePh         4-PrOPh      C═O                                   1-595   3-MePh         3- iBuOPh    C═O                                   1-596   3-MePh         4- iBuOPh    C═O                                   1-597   4-MePh         Ph           C═O                                   1-598   4-MePh         3,4-diMeOPh  C═O                                   1-599   4-MePh         3-MeOPh      C═O                                   1-600   4-MePh         4-MeOPh      C═O                                   1-601   4-MePh         3,4-diPrOPh  C═O                                   1-602   4-MePh         3-MeO-4-PrOPh                                                                              C═O                                   1-603   3-MeO-4-PrOPh  Ph           C═O                                   1-604   3-MeO-4-PrOPh  2-Np         C═O                                   1-605   3-MeO-4-PrOPh  3-Np         C═O                                   1-606   3,4-diPrOPh    Ph           C═O                                   1-607   3-MeOPh        Ph           C═O                                   1-608   3-PrOPh        Ph           C═O                                   1-609   4-PrOPh        Ph           C═O                                   1-610   3- iBuOPh      Ph           C═O                                   1-611   4- iBuOPh      Ph           C═O                                   1-612   3-EtPh         Ph           C═O                                   1-613   3-EtPh         1-Np         C═O                                   1-614   3-EtPh         2-Np         C═O                                   1-615   3-PrPh         Ph           C═O                                   1-616   3-PrPh         1-Np         C═O                                   1-617   3-PrPh         2-Np         C═O                                   1-618   3- iBuPh       Ph           C═O                                   1-619   3- iBuPh       1-Np         C═O                                   1-620   3-iBuPh        2-Np         C═O                                   1-621   3,4-diMePh     Ph           C═O                                   1-622   Ph             3-MeO-4-EtOPh                                                                              C═O                                   1-623   Ph             3-MeO-4-EtOPh                                                                              C═S                                   1-624   Ph             3-MeO-4-EtOPh                                                                              CH.sub.2                                  1-625   Ph             3-MeO-4-PrOPh                                                                              C═S                                   1-626   Ph             3-MeO-4-PrOPh                                                                              CH.sub.2                                  1-627   Ph             3-MeO-4-BuOPh                                                                              C═O                                   1-628   Ph             3-MeO-4-PnOPh                                                                              C═O                                   1-629   Ph             3-MeO-4-HxOPh                                                                              C═O                                   1-630   Ph             3-EtO-4-MeOPh                                                                              C═O                                   1-631   Ph             3-PrO-4-MeOPh                                                                              C═O                                   1-632   Ph             3-BuO-4-MeOPh                                                                              C═O                                   1-633   Ph             3-PnO-4-MeOPh                                                                              C═O                                   1-634   Ph             3-HxO-4-MeOPh                                                                              C═O                                   1-635   Ph             3,4-diMeOPh  C═S                                   1-636   Ph             3,4-diMeOPh  CH.sub.2                                  1-637   Ph             3,4-diEtOPh  C═O                                   1-638   Ph             3,4-diPrOPh  C═S                                   1-639   Ph             3,4-diPrOPh  CH.sub.2                                  1-640   Ph             3,4-diBuOPh  C═O                                   1-641   Ph             4-EtOPh      C═O                                   1-642   Ph             4-BuOPh      C═O                                   1-643   Ph             4-PnOPh      C═O                                   1-644   Ph             4-HxOPh      C═O                                   1-645   Ph             3-MeOPh      C═O                                   1-646   Ph             3-EtOPh      C═O                                   1-647   Ph             3-BuOPh      C═O                                   1-648   Ph             3-BuPh       C═O                                   1-649   Ph             4-BuPh       C═O                                   1-650   Ph             3-PnPh       C═O                                   1-651   Ph             3-HxPh       C═O                                   1-652   Ph             3,4-diEtPh   C═O                                   1-653   Ph             3,4-diPrPh   C═O                                   1-654   Ph             3,4-diBuPh   C═O                                   1-655   3-BuOPh        3-BuOPh      C═O                                   1-656   4-ClPh         2,3-diMeOPh  C═O                                   1-657   2,3-diClPh     3-BuPh       C═O                                   1-658   2,3-diClPh     4-BuPh       C═O                                   1-659   3,4-diClPh     3-EtPh       C═O                                   1-660   3,4-diClPh     4-EtPh       C═O                                   1-661   3,4-diClPh     3-BuPh       C═O                                   1-662   3,4-diClPh     4-BuPh       C═O                                   1-663   3,4-diClPh     4-MeOPh      C═S                                   1-664   3,4-diClPh     4-MeOPh      CH.sub.2                                  1-665   3,4-diClPh     4-PrOPh      C═S                                   1-666   3,4-diClPh     3-PrOPh      CH.sub.2                                  1-667   3,4-diClPh     3-BuOPh      C═O                                   1-668   3,4-diClPh     4-BuOPh      C═O                                   1-669   3,4-diClPh     3,4-diMeOPh  C═O                                   1-670   3-TfmPh        3-EtOPh      C═O                                   1-671   3-TfmPh        4-EtOPh      C═O                                   1-672   3-TfmPh        3-BuOPh      C═O                                   1-673   3-TfmPh        3-PnOPh      C═O                                   1-674   3-TfmPh        3-HxOPh      C═O                                   1-675   3-TfmPh        4-BuOPh      C═O                                   1-676   3-TfmPh        4-PnOPh      C═O                                   1-677   3-TfmPh        4-HxOPh      C═O                                   1-678   3-TfmPh        4-BuPh       C═O                                   1-679   3-TfmPh        3-EtO-4-MeOPh                                                                              C═O                                   1-680   3-TfmPh        3-PrO-4-MeOPh                                                                              C═O                                   1-681   3-TImPh        3-BuO-4-MeOPh                                                                              C═O                                   1-682   3-TfmPh        3-PnO-4-MeOPh                                                                              C═O                                   1-683   3-TfmPh        3-HxO-4-MeOPh                                                                              C═O                                   1-684   3-TfmPh        3-MeO-4-EtOPh                                                                              C═O                                   1-685   3-TfmPh        3-MeO-4-PrOPh                                                                              C═O                                   1-686   3-TfmPh        3-MeO-4-PrOPh                                                                              C═S                                   1-687   3-TfmPh        3-MeO-4-PrOPh                                                                              CH.sub.2                                  1-688   3-TfmPh        3-MeO-4-BuOPh                                                                              C═O                                   1-689   3-TfmPh        3-MeO-4-PnOPh                                                                              C═O                                   1-690   3-TfmPh        3-MeO-4-HxOPh                                                                              C═O                                   1-691   3-TfmPh        3,4-diMeOPh  C═S                                   1-692   3-TfmPh        3,4-diMeOPh  CH.sub.2                                  1-693   3-TfmPh        3,4-diEtOPh  C═O                                   1-694   3-TfmPh        3,4-diPrOPh  C═O                                   1-695   3-TfmPh        3,4-diPrOPh  C═S                                   1-696   3-TfmPh        3,4-diPrOPh  CH.sub.2                                  1-697   3-TfmPh        3,4-diBuOPh  C═O                                   1-698   3-MePh         3-MePh       C═S                                   1-699   3-MePh         3-MePh       CH.sub.2                                  1-700   3-MePh         3-BuPh       C═O                                   1-701   3-MePh         4-BuPh       C═O                                   1-702   3-MePh         3-EtOPh      C═O                                   1-703   3-MePh         4-EtOPh      C═O                                   1-704   3-MePh         3-BuOPh      C═O                                   1-705   3-MePh         3-PnOPh      C═O                                   1-706   3-MePh         3-HxOPh      C═O                                   1-707   3-MePh         4-BuOPh      C═O                                   1-708   3-MePh         4-PnOPh      C═O                                   1-709   3-MePh         4-HxOPh      C═O                                   1-710   3-MePh         3-MeO-4-PrOPh                                                                              C═O                                   1-711   3-MePh         3-MeO-4-PrOPh                                                                              C═S                                   1-712   3-MePh         3-MeO-4-PrOPh                                                                              CH.sub.2                                  1-713   3-MePh         3-MeO-4-EtOPh                                                                              C═O                                   1-714   3-MePh         3-MeO-4-BuOPh                                                                              C═O                                   1-715   3-MePh         3-MeO-4-PnOPh                                                                              C═O                                   1-716   3-MePh         3-MeO-4-HxOPh                                                                              C═O                                   1-717   3-MePh         3-EtO-4-MeOPh                                                                              C═O                                   1-718   3-MePh         3-PrO-4-MeOPh                                                                              C═O                                   1-719   3-MePh         3-BuO-4-MeOPh                                                                              C═O                                   1-720   3-MePh         3-PnO-4-MeOPh                                                                              C═O                                   1-721   3-MePh         3-HxO-4-MeOPh                                                                              C═O                                   1-722   3-MePh         3,4-diMeOPh  C═S                                   1-723   3-MePh         3,4-diMeOPh  CH.sub.2                                  1-724   3-MePh         3,4-diEtOPh  C═O                                   1-725   3-MePh         3,4-diPrOPh  C═O                                   1-726   3-MePh         3,4-diBuOPh  C═O                                   1-727   3,4-methylenedioxyPh                                                                         Ph           C═O                                   1-728   3,4-methylenedioxyPh                                                                         3-ClPh       C═O                                   1-729   3,4-methylenedioxyPh                                                                         3,4-diClPh   C═O                                   1-730   3,4-methylenedioxyPh                                                                         3-MePh       C═O                                   1-731   3,4-methylenedioxyPh                                                                         3-TfmPh      C═O                                   1-732   3-ClPh         3-EtOPh      C═O                                   1-733   3-ClPh         4-EtOPh      C═O                                   1-734   3-ClPh         3-BuOPh      C═O                                   1-735   3-ClPh         3-PnOPh      C═O                                   1-736   3-ClPh         3-HxOPh      C═O                                   1-737   3-ClPh         4-BuOPh      C═O                                   1-738   3-ClPh         4-PnOPh      C═O                                   1-739   3-ClPh         4-HxOPh      C═O                                   1-740   3-ClPh         3-MeO-4-PrOPh                                                                              C═O                                   1-741   3-ClPh         3-MeO-4-PrOPh                                                                              C═S                                   1-742   3-ClPh         3-MeO-4-PrOPh                                                                              CH.sub.2                                  1-743   3-ClPh         3-MeO-4-EtOPh                                                                              C═O                                   1-744   3-ClPh         3-MeO-4-PnOPh                                                                              C═O                                   1-745   3-ClPh         3-MeO-4-HxOPh                                                                              C═O                                   1-746   3-ClPh         3-EtO-4-MeOPh                                                                              C═O                                   1-747   3-ClPh         3-BuO-4-MeOPh                                                                              C═O                                   1-748   3-ClPh         3-PnO-4-MeOPh                                                                              C═O                                   1-749   3-ClPh         3-HxO-4-MeOPh                                                                              C═O                                   1-750   3-ClPh         3,4-diMeOPh  C═S                                   1-751   3-ClPh         3,4-diMeOPh  CH.sub.2                                  1-752   3-ClPh         3,4-diEtOPh  C═O                                   1-753   3-ClPh         3,4-diPrOPh  C═S                                   1-754   3-ClPh         3,4-diPrOPh  CH.sub.2                                  1-755   3-ClPh         3,4-diBuOPh  C═O                                   1-756   3-ClPh         3-BuPh       C═O                                   1-757   3-ClPh         4-BuPh       C═O                                   1-758   1-Np           3-ClPh       C═O                                   1-759   2-Np           3-ClPh       C═O                                   1-760   1-Np           3,4-diClPh   C═O                                   1-761   2-Np           3,4-diClPh   C═O                                   1-762   1-Np           3-TfmPh      C═O                                   1-763   2-Np           3-TfmPh      C═O                                   1-764   3-BrPh         3-BrPh       C═O                                   1-765   3-BrPh         3-MeOPh      C═O                                   1-766   3-BrPh         3-EtOPh      C═O                                   1-767   3-BrPh         3-PrOPh      C═O                                   1-768   3-BrPh         3-BuOPh      C═O                                   1-769   3-BrPh         3-PnOPh      C═O                                   1-770   3-BrPh         3-HxOPh      C═O                                   1-771   3-BrPh         4-MeOPh      C═O                                   1-772   3-BrPh         4-EtOPh      C═O                                   1-773   3-BrPh         4-PrOPh      C═O                                   1-774   3-BrPh         4-BuOPh      C═O                                   1-775   3-BrPh         4-PnOPh      C═O                                   1-776   3-BrPh         4-HxOPh      C═O                                   1-777   3-BrPh         3-MeO-4-EtOPh                                                                              C═O                                   1-778   3-BrPh         3-MeO-4-PrOPh                                                                              C═O                                   1-779   3-BrPh         3-MeO-4-BuOPh                                                                              C═O                                   1-780   3-BrPh         3-EtO-4-MeOPh                                                                              C═O                                   1-781   3-BrPh         3-PrO-4-MeOPh                                                                              C═O                                   1-782   3-BrPh         3-BuO-4-MeOPh                                                                              C═O                                   1-783   3-BrPh         3,4-diEtOPh  C═O                                   1-784   3-BrPh         3,4-diPrOPh  C═O                                   1-785   3-BrPh         3-MePh       C═O                                   1-786   3-BrPh         3-EtPh       C═O                                   1-787   3-BrPh         4-MePh       C═O                                   1-788   3-BrPh         4-EtPh       C═O                                   1-789   3-BrPh         1-Np         C═O                                   1-790   3-BrPh         2-Np         C═O                                   1-791   3,5-diClPh     3-MeOPh      C═O                                   1-792   3,5-diClPh     3-PrOPh      C═O                                   1-793   3,5-diClPh     4-MeOPh      C═O                                   1-794   3,5-diClPh     4-PrOPh      C═O                                   1-795   3,5-diClPh     3-EtPh       C═O                                   1-796   3,5-diClPh     4-EtPh       C═O                                   1-797   3,5-diClPh     3-PrPh       C═O                                   1-798   3,5-diClPh     4-PrPh       C═O                                   1-799   3,5-diClPh     4-EtOPh      C═O                                   1-800   3,5-diClPh     3,4-diCH.sub.3 O--Ph                                                                       C═O                                   1-801   2,3-diClPh     4-EtOPh      C═O                                   1-802   2,5-diClPh     3-CH.sub.3 OPh                                                                             C═O                                   1-803   2.5-diClPh     4-CH.sub.3 OPh                                                                             C═O                                   1-804   2,5-diClPh     3-EtOPh      C═O                                   1-805   2,5-diClPh     4-EtOPh      C═O                                   1-806   2,5-diClPh     3-PrOPh      C═O                                   1-807   2,5-diClPh     4-PrOPh      C═O                                   1-808   2,5-diClPh     4-CH.sub.3 Ph                                                                              C═O                                   1-809   2,5-diClPh     4-EtPh       C═O                                   1-810   2,5-diClPh     4-PrPh       C═O                                   1-811   2,5-diClPh     3,4-diCH.sub.3 O--Ph                                                                       C═O                                   1-812   2,6-diClPh     3-CH.sub.3 OPh                                                                             C═O                                   1-813   2,6-diClPh     4-CH.sub.3 OPh                                                                             C═O                                   1-814   2,6-diClPh     3-EtOPh      C═O                                   1-815   2,6-diClPh     4-EtOPh      C═O                                   1-816   2,6-diClPh     3-PrOPh      C═O                                   1-817   2,6-diClPh     4-PrOPh      C═O                                   1-818   2,6-diClPh     3,4-diCH.sub.3 O--Ph                                                                       C═O                                   1-819   2,6-diClPh     4-CH.sub.3 Ph                                                                              C═O                                   1-820   2,6-diClPh     4-EtPh       C═O                                   1-821   2,6-diClPh     4-PrPh       C═O                                   1-822   2,4-diClPh     3-CH.sub.3 OPh                                                                             C═O                                   1-823   2,4-diClPh     4-CH.sub.3 OPh                                                                             C═O                                   1-824   2,4-diClPh     3-EtOPh      C═O                                   1-825   2,4-diClPh     4-EtOPh      C═O                                   1-826   2,4-diClPh     3-PrOPh      C═O                                   1-827   2,4-diClPh     4-PrOPh      C═O                                   1-828   2,4-diClPh     3,4-diCH.sub.3 O--Ph                                                                       C═O                                   1-829   2,4-diClPh     4-CH.sub.3 Ph                                                                              C═O                                   1-830   2,4-diClPh     4-EtPh       C═O                                   1-831   2,4-diClPh     4-PrPh       C═O                                   1-832   3,5-diCH.sub.3 Ph                                                                            4-CH.sub.3 OPh                                                                             C═O                                   1-833   3,5-diCH.sub.3 Ph                                                                            4-EtOPh      C═O                                   1-834   3,5-diCH.sub.3 Ph                                                                            4-PrOPh      C═O                                   1-835   3,5-diCH.sub.3 Ph                                                                            3,4-diCH.sub.3 O--Ph                                                                       C═O                                   1-836   3,5-diCH.sub.3 Ph                                                                            4-CH.sub.3 Ph                                                                              C═O                                   1-837   3,5-diCH.sub.3 Ph                                                                            4-EtPh       C═O                                   1-838   3,5-diCH.sub.3 Ph                                                                            4-PrPh       C═O                                   1-839   3,5-diCH.sub.3 Ph                                                                            3-ClPh       C═O                                   1-840   3,5-diCH.sub.3 Ph                                                                            4-ClPh       C═O                                   1-841   3,5-diCH.sub.3 Ph                                                                            3-FPh        C═O                                   1-842   3,5-diCH.sub.3 Ph                                                                            4-FPh        C═O                                   1-843   3,5-diCH.sub.3 Ph                                                                            3-BrPh       C═O                                   1-844   3,5-diCH.sub.3 Ph                                                                            4-BrPh       C═O                                   1-845   3,5-diCF.sub.3 Ph                                                                            4-CH.sub.3 OPh                                                                             C═O                                   1-846   3,5-diCF.sub.3 Ph                                                                            4-EtOPh      C═O                                   1-847   3,5-diCF.sub.3 Ph                                                                            4-PrOPh      C═O                                   1-848   3,5-diCF.sub.3 Ph                                                                            3,4-diCH.sub.3 O--Ph                                                                       C═O                                   1-849   3,5-diCF.sub.3 Ph                                                                            4-CH.sub.3 Ph                                                                              C═O                                   1-850   3,5-diCF.sub.3 Ph                                                                            4-EtPh       C═O                                   1-851   3,5-diCF.sub.3 Ph                                                                            4-PrPh       C═O                                   1-852   3,5-diCF.sub.3 Ph                                                                            3-ClPh       C═O                                   1-853   3,5-diCF.sub.3 Ph                                                                            4-ClPh       C═O                                   1-854   3,3-diCF.sub.3 Ph                                                                            3-FPh        C═O                                   1-855   3,5-diCF.sub.3 Ph                                                                            4-FPh        C═O                                   1-856   3,5-diCF.sub.3 Ph                                                                            3-BrPh       C═O                                   1-857   3,5-diCF.sub.3 Ph                                                                            4-BrPh       C═O                                   1-858   3,5-diFPh      4-CH.sub.3 OPh                                                                             C═O                                   1-859   3,5-diFPh      4-EtOPh      C═O                                   1-860   3,5-diFPh      4-PrOPh      C═O                                   1-861   3,5-diFPh      4-CH.sub.3 Ph                                                                              C═O                                   1-862   3,5-diFPh      4-EtPh       C═O                                   1-863   3,5-diFPh      4-PrPh       C═O                                   1-864   3,5-diFPh      3-ClPh       C═O                                   1-865   3,5-diFPh      4-ClPh       C═O                                   1-866   3-Cl-5-F--Ph   4-CH.sub.3 OPh                                                                             C═O                                   1-867   3-Cl-5-F--Ph   4-EtOPh      C═O                                   1-868   3-Cl-5-F--Ph   4-EtPh       C═O                                   1-869   3-Cl-5-F--Ph   4-PrPh       C═O                                   1-870   3,5-diBrPh     4-CH.sub.3 OPh                                                                             C═O                                   1-871   3-FPh          4-EtPh       C═O                                   1-872   3-FPh          4-EtOPh      C═O                                   1-873   3-Cl-5-CH.sub.3 Ph                                                                           4-CH.sub.3 OPh                                                                             C═O                                   1-874   3-Cl-5-CH.sub.3 Ph                                                                           4-EtOPh      C═O                                   1-875   3-Cl-5-CH.sub.3 Ph                                                                           4-EtPh       C═O                                   1-876   3-Cl-5-CH.sub.3 Ph                                                                           4-PrPh       C═O                                   ______________________________________                                    

                                      TABLE 2                                     __________________________________________________________________________    Compound                                                                      No.    R.sup.1   R.sup.2    R.sup.4                                           __________________________________________________________________________    2-1    3-ClPh    3-ClPh     3, 4-diMeOPh                                      2-2    4-ClPh    4-ClPh     3, 4-diMeOPh                                      2-3    3-ClPh    2, 3-diClPh                                                                              3, 4-diMeOPh                                      2-4    3-ClPh    3, 4-diClPh                                                                              3, 4-diMeOPh                                      2-5    4-ClPh    2, 3-diClPh                                                                              3, 4-dtMeOPh                                      2-6    3-ClPh    3-MeOPh    3, 4-diMeOPh                                      2-7    3-ClPh    4-MeOPh    3, 4-diMeOPh                                      2-8    3-ClPh    3, 4-diMeOPh                                                                             3, 4-diMeOPh                                      2-9    3-ClPh    3-MeO-3-PrOPh                                                                            3, 4-diMeOPh                                      2-10   2, 3-diClPh                                                                             3-MeOPh    3, 4-diMeOPh                                      2-11   2, 3-diClPh                                                                             4-MeOPh    3, 4-diMeOPh                                      2-12   2, 3-diClPh                                                                             3-MePh     3, 4-diMeOPh                                      2-13   2, 3-diClPh                                                                             4-MePh     3, 4-diMeOPh                                      2-14   3, 4-diClPh                                                                             3-MeOPh    3, 4-diMeOPh                                      2-15   3, 4-diClPh                                                                             4-MeOPh    3, 4-diMeOPh                                      2-16   3, 4-diClPh                                                                             4-PrOPh    3, 4-diMeOPh                                      2-17   3, 4-diClPh                                                                             4- iBuOPh  3, 4-diMeOPh                                      2-18   3, 4-diClPh                                                                             3-MePh     3, 4-diMeOPh                                      2-19   3, 4-diClPh                                                                             4-MePh     3, 4-diMeOPh                                      2-20   3, 4-diClPh                                                                             4- iBuPh   3, 4-diMeOPh                                      2-21   3-MePh    3-MePh     3, 4-diMeOPh                                      2-22   3-MePh    4-MePh     3, 4-diMeOPh                                      2-23   3-MePh    4-MeOPh    3, 4-diMeOPh                                      2-24   3-MePh    3-PrOPh    3, 4-diMeOPh                                      2-25   3-MePh    4-PrOPh    3, 4-diMeOPh                                      2-26   3-MePh    3- iBuOPh  3, 4-diMeOPh                                      2-27   3-MePh    4- iBuOPh  3, 4-diMeOPh                                      2-28   3-MePh    3, 4-diMePh                                                                              3, 4-diMeOPh                                      2-29   3-MePh    3, 4-diMeOPh                                                                             3, 4-diMeOPh                                      2-30   3-MePh    3, 4-diPrOPh                                                                             3, 4-diMeOPh                                      2-31   3-MePh    3-MeO-4-PrOPh                                                                            3, 4-diMeOPh                                      2-32   3-TfmPh   3-ClPh     3, 4-diMeOPh                                      2-33   3-TfmPh   4-ClPh     3, 4-diMeOPh                                      2-34   3-TfmPh   3-MeOPh    3, 4-diMeOPh                                      2-35   3-TfmPh   4-MeOPh    3, 4-diMeOPh                                      2-36   3-TfmPh   3-PrOPh    3, 4-diMeOPh                                      2-37   3-TfmPh   4-PrOPh    3, 4-diMeOPh                                      2-38   3-TfmPh   3- iBuOPh  3, 4-diMeOPh                                      2-39   3-TfmPh   4- iBuOPh  3, 4-diMeOPh                                      2-40   3-TfmPh   3, 4-diMeOPh                                                                             3, 4-diMeOPh                                      2-41   3-ClPh    3-ClPh     3-MeOPh                                           2-42   3-ClPh    4-ClPh     3-MeOPh                                           2-43   3-ClPh    3-MeOPh    3-MeOPh                                           2-44   3-ClPh    4-MeOPh    3-MeOPh                                           2-45   3-ClPh    3, 4-diMeOPh                                                                             3-MeOPh                                           2-46   3, 4-diClPh                                                                             4-MeOPh    3-MeOPh                                           2-47   3, 4-diClPh                                                                             4-PrOPh    3-MeOPh                                           2-48   3, 4-diClPh                                                                             4- iBuOPh  3-MeOPh                                           2-49   3-MePh    3-MePh     3-MeOPh                                           2-50   3-MePh    4-MeOPh    3-MeOPh                                           2-51   3-MePh    4-PrOPh    3-MeOPh                                           2-52   3-MePh    4- iBuOPh  3-MeOPh                                           2-53   3-MePh    3, 4-diMeOPh                                                                             3-MeOPh                                           2-54   3-MePh    3, 4-diClPh                                                                              3-MeOPh                                           2-55   3-MePh    3, 4-diMePh                                                                              3-MeOPh                                           2-56   3-TfmPh   4-MeOPh    3-MeOPh                                           2-57   3-TfmPh   4-PrOPh    3-MeOPh                                           2-58   3-TfmPh   4- iBuOPh  3-MeOPh                                           2-59   3-TfmPh   3, 4-diMeOPh                                                                             3-MeOPh                                           2-60   3-TfmPh   3, 4-diClPh                                                                              3-MeOPh                                           2-61   3-TfmPh   3, 4-diMePh                                                                              3-MeOPh                                           2-62   3-ClPh    3-ClPh     4-MeOPh                                           2-63   3-ClPh    4-ClPh     4-MeOPh                                           2-64   3-ClPh    3-MeOPh    4-MeOPh                                           2-65   3-ClPh    4-MeOPh    4-MeOPh                                           2-66   3-ClPh    3, 4-diMePh                                                                              4-MeOPh                                           2-67   3, 4-diClPh                                                                             4-MeOPh    4-MeOPh                                           2-68   3, 4-diClPh                                                                             4-PrOPh    4-MeOPh                                           2-69   3, 4-diClPh                                                                             4- iBuOPh  4-MeOPh                                           2-70   3-MePh    3-MePh     4-MeOPh                                           2-71   3-MePh    4-MeOPh    4-MeOPh                                           2-72   3-MePh    4-PrOPh    4-MeOPh                                           2-73   3-MePh    4- iBuOPh  4-MeOPh                                           2-74   3-MePh    3, 4-diMeOPh                                                                             4-MeOPh                                           2-75   3-MePh    3, 4-diClPh                                                                              4-MeOPh                                           2-76   3-MePh    3, 4-diMePh                                                                              4-MeOPh                                           2-77   3-TfmPh   4-MeOPh    4-MeOPh                                           2-78   3-TfmPh   4-PrOPh    4-MeOPh                                           2-79   3-TfmPh   4- iBuOPh  4-MeOPh                                           2-80   3-TfmPh   3, 4-diMeOPh                                                                             4-MeOPh                                           2-81   3-TfmPh   3, 4-diClPh                                                                              4-MeOPh                                           2-82   3-TfmPh   3, 4-diMePh                                                                              4-MeOPh                                           2-83   Ph        3, 4-diMeOPh                                                                             3, 4-diMeOPh                                      2-84   Ph        3, 4-diMeOPh                                                                             3-MeOPh                                           2-85   Ph        3, 4-diMeOPh                                                                             4-MeOPh                                           2-86   Ph        3, 4-diPrOPh                                                                             3, 4-diMeOPh                                      2-87   Ph        3, 4-diPrOPh                                                                             3-MeOPh                                           2-88   Ph        3, 4-diPrOPh                                                                             4-MeOPh                                           2-89   Ph        3-MeO-4-PrOPh                                                                            3, 4-diMeOPh                                      2-90   Ph        3-MeO-4-PrOPh                                                                            3-MeOPh                                           2-91   Ph        3-MeO-4-PrOPh                                                                            4-MeOPh                                           2-92   3-ClPh    3, 4-diPrOPh                                                                             3, 4-diMeOPh                                      2-93   3-ClPh    3, 4-diPrOPh                                                                             3-MeOPh                                           2-94   3-ClPh    3, 4-diPrOPh                                                                             4-MeOPh                                           2-95   3-ClPh    3-PrO-4-MeOPh                                                                            3, 4-diMeOPh                                      2-96   3-ClPh    3-PrO-4-MeOPh                                                                            3-MeOPh                                           2-97   3-ClPh    3-PrO-4-MeOPh                                                                            4-MeOPh                                           2-98   3-MePh    3-PrO-4-MeOPh                                                                            3, 4-diMeOPh                                      2-99   3-MePh    3-PrO-4-MeOPh                                                                            3-MeOPh                                           2-100  3-MePh    3-PrO-4-MeOPh                                                                            4-MeOPh                                           2-101  3-TfmPh   3-MeO-4-PrOPh                                                                            3, 4-diMeOPh                                      2-102  3-TfmPh   3-MeO-4-PrOPh                                                                            3-MeOPh                                           2-103  3-TfmPh   3-MeO-4-PrOPh                                                                            4-MeOPh                                           2-104  3-TfmPh   3-PrO-4-MeOPh                                                                            3, 4-diMeOPh                                      2-105  3-TfmPh   3-PrO-4-MeOPh                                                                            3-MeOPh                                           2-106  3-Tfmph   3-PrO-4-MeOPh                                                                            4-MeOPh                                           2-107  3-TfmPh   3, 4-diPrOPh                                                                             3, 4-diMeOPh                                      2-108  3-TfmPh   3, 4-diPrOPh                                                                             3-MeOPh                                           2-109  3-TfmPh   3, 4-diPrOPh                                                                             4-MeOPh                                           2-110  3, 4-diMeOPh                                                                            Ph         3, 5-diMeO-4-PrSPh                                2-111  3, 4-diMeOPh                                                                            Ph         4-MeSPh                                           2-112  3-MeO-4-PrOPh                                                                           Ph         3-MeS-4, 5-diMeOPh                                2-113  3-MeO-4-PrOPh                                                                           3-MePh     3, 4, 5-triMePh                                   2-114  3-MeO-4-PrOPh                                                                           3-MePh     3, 4, 5-triEtPh                                   2-115  3-MeO-4-PrOPh                                                                           3-ClPh     3, 4-diEtPh                                       2-116  3-MeO-4-PrOPh                                                                           3-TfmPh    4-EtPh                                            2-117  4-PrOPh   3, 4-diClPh                                                                              4-ClPh                                            2-118  4-PrOPh   3-MePh     3, 4-diClPh                                       2-119  3-PrOPh   3-TfmPh    3-ClPh                                            2-120  3-ClPh    3-ClPh     3-Cl-4-MePh                                       2-121  3-MePh    3-MePh     3-Me-4-ClPh                                       2-122  3-MePh    3-MePh     Ph                                                2-123  3-MeOPh   Ph         2-TfmPh                                           2-124  3-EtOPh   Ph         3-TfmPh                                           2-125  4-MeOPh   Ph         4-TfmPh                                           2-126  4-EtOPh   Ph         3, 4, 5-triTfmPh                                  2-127  3, 4-diMeOPh                                                                            Ph         2-TfmPh                                           2-128  3, 4-diEtOPh                                                                            Ph         3-TfmPh                                           2-129  3-MeOPh   4-ClPh     4-TfmPh                                           2-130  3-EtOPh   4-BrPh     3, 4, 5-triTfmPh                                  2-131  4-MeOPh   4-FPh      2-TfmPh                                           2-132  4-EtOPh   4-ClPh     3-TfmPh                                           2-133  3, 4-diMeOPh                                                                            4-FPh      4-TfmPh                                           2-134  3, 4-diEtOPh                                                                            4-BrPh     3, 4, 5-triTfmPh                                  2-135  3-MeOPh   4-MePh     2-TfmPh                                           2-136  3-EtOPh   4-MePh     3-TfmPh                                           2-137  4-MeOPh   4-MePh     4-TfmPh                                           2-138  4-EtOPh   4-MePh     3, 4, 5-triTfmPh                                  2-139  3, 4-diMeOPh                                                                            4-MePh     2-TfmPh                                           2-140  3, 4-diEtOPh                                                                            4-MePh     3-TfmPh                                           2-141  3-MeOPh   4-TfmPh    4-TfmPh                                           2-142  3-EtOPh   4-TfmPh    3, 4, 5-triTfmPh                                  2-143  4-MeOPh   4-TfmRh    2-TfmPh                                           2-144  4-EtOPh   4-TfmPh    3-TfmPh                                           2-145  3, 4-diMeOPh                                                                            4-TfmPh    4-TfmPh                                           2-146  3, 4-diEtOPh                                                                            4-TfmPh    3, 4, 5-triTfmPh                                  2-147  3-MeOPh   3, 4-diClPh                                                                              2-TfmPh                                           2-148  3-EtOPh   3, 4-diFPh 3-TfmPh                                           2-149  4-MeOPh   3, 4-diFPh 4-TfmPh                                           2-150  4-EtOPh   3, 4-diClPh                                                                              3, 4, 5-triTfmPh                                  2-151  3, 4-diMeOPh                                                                            3, 4-diClPh                                                                              2-TfmPh                                           2-152  3, 4-diEtOPh                                                                            3, 4-diFPh 3-TfmPh                                           2-153  3-MeOPh   Ph         2-EtOPh                                           2-154  3-EtOPh   Ph         3-EtOPh                                           2-155  4-MeOPh   Ph         4-EtOPh                                           2-156  4-EtOPh   Ph         2, 3, 4-triEtOPh                                  2-157  3, 4-diMeOPh                                                                            Ph         2-HOPh                                            2-158  3, 4-diEtOPh                                                                            Ph         3-HOPh                                            2-159  3-MeOPh   4-ClPh     4-HOPh                                            2-160  3-EtOPh   4-BrPh     3, 4, 5-triHOPh                                   2-161  4-MeOPh   4-FPh      2-MeSPh                                           2-162  4-EtOPh   4-ClPh     3-MeSPh                                           2-163  3, 4-diMeOPh                                                                            4-FPh      4-MeSPh                                           2-164  3, 4-diEtOPh                                                                            4-BrPh     3, 4, 5-triMeSPh                                  2-165  3-MeOPh   4-MePh     3, 4, 5-triEtSPh                                  2-166  3-EtOPh   4-MePh     2-EtOPh                                           2-167  4-MeOPh   4-MePh     3-EtOPh                                           2-168  4-EtOPh   4-MePh     4-EtOPh                                           2-169  3, 4-diMeOPh                                                                            4-MePh     2, 3, 4-triEtOPh                                  2-170  3, 4-diEtOPh                                                                            4-MePh     2-HOPh                                            2-171  3-MeOPh   4-TfmPh    3-HOPh                                            2-172  3-EtOPh   4-TfmPh    4-HOPh                                            2-173  4-MeOPh   4-TfmPh    3, 4, 5-triHOPh                                   2-174  4-EtOPh   4-TfmPh    2-MeSPh                                           2-175  3, 4-diMeOPh                                                                            4-TfmPh    3-MeSPh                                           2-176  3, 4-diEtOPh                                                                            4-TfmPh    4-MeSPh                                           2-177  3-MeOPh   3, 4-diClPh                                                                              3, 4, 5-triMeSPh                                  2-178  3-MeOPh   3, 4-diFPh 3, 4, 5-triEtSPh                                  2-179  4-MeOPh   3, 4-diFPh 2-EtOPh                                           2-180  4-EtOPh   3, 4-diClPh                                                                              3-EtOPh                                           2-181  3, 4-diMeOPh                                                                            3, 4-diClPh                                                                              4-EtOPh                                           2-182  3, 4-diEtOPh                                                                            3, 4-diFPh 3, 4, 5-triEtOPh                                  2-183  3-MeOPh   Ph         2-ClPh                                            2-184  3-EtOPh   Ph         3-ClPh                                            2-185  4-MeOPh   Ph         4-ClPh                                            2-186  4-EtOPh   Ph         3, 4, 5-triClPh                                   2-187  3, 4-diMeOPh                                                                            Ph         2-FPh                                             2-188  3, 4-diEtOPh                                                                            Ph         3-FPh                                             2-189  3-MeOPh   4-ClPh     4-FPh                                             2-190  3-EtOPh   4-BrPh     3, 4, 5-triFPh                                    2-191  4-MeOPh   4-FPh      2-BrPh                                            2-192  4-EtOPh   4-ClPh     3-BrPh                                            2-193  3, 4-diMeOPh                                                                            4-FPh      4-BrPh                                            2-194  3, 4-diEtOPh                                                                            4-BrPh     3, 4, 5-triBrPh                                   2-195  3-MeOPh   4-MePh     2-ClPh                                            2-196  3-EtOPh   4-MePh     3-ClPh                                            2-197  4-MeOPh   4-MePh     4-ClPh                                            2-198  4-EtOPh   4-MePh     3, 4, 5-triClPh                                   2-199  3, 4-diMeOPh                                                                            4-MePh     2-FPh                                             2-200  3, 4-diEtOPh                                                                            4-MePh     3-FPh                                             2-201  3-MeOPh   4-TfmPh    4-FPh                                             2-202  3-EtOPh   4-TfmPh    3, 4, 5-triFPh                                    2-203  4-MeOPh   4-TfmPh    2-BrPh                                            2-204  4-EtOPh   4-TfmPh    3-BrPh                                            2-205  3, 4-diMeOPh                                                                            4-TfmPh    4-BrPh                                            2-206  3, 4-diEtOPh                                                                            4-TfmPh    3, 4, 3-triBrPh                                   2-207  3-MeOPh   3, 4-diClPh                                                                              2-ClPh                                            2-208  3-EtOPh   3, 4-diFPh 3-ClPh                                            2-209  4-MeOPh   3, 4-diFPh 4-ClPh                                            2-210  4-EtOPh   3, 4-diClPh                                                                              3, 4, 5-triClPh                                   2-211  3, 4-diMeOPh                                                                            3, 4-diClPh                                                                              2-FPh                                             2-212  3, 4-diEtOPh                                                                            3, 4-diFPh 3-FPh                                             __________________________________________________________________________

                  TABLE 3                                                         ______________________________________                                        Compound                                                                      No.     R.sup.1   R.sup.2      R.sup.4                                        ______________________________________                                        3-1     Ph        3, 4-diMeOPh 3, 4, 5-triMeOPh                               3-2     3-ClPh    3, 4-diMeOPh 3, 4, 5-triMeOPh                               3-3     3-TfmPh   3, 4-diMeOPh 3, 4, 5-triMeOPh                               3-4     3-MePh    3, 4-diMeOPh 3, 4, 5-triMeOPh                               3-5     4-MeOPh   3, 4-diClPh  3, 4, 5-triMeOPh                               3-6     4-MeOPh   3, 4-diMePh  3, 4, 5-triMeOPh                               3-7     3-ClPh    3-ClPh       3, 4, 5-triMeOPh                               3-8     3-MePh    3-MePh       3, 4, 5-triMeOPh                               3-9     3-ClPh    3-PrOPh      3, 4, 5-triMeOPh                               3-10    3-ClPh    4- iBuOPh    3, 4, 5-triMeOPh                               3-11    3-MePh    4-PrOPh      3, 4, 5-triMeOPh                               3-12    3-MePh    4- iBuOPh    3, 4, 5-triMeOPh                               3-13    3, 4-diClPh                                                                             4-PrOPh      3, 4, 5-triMeOPh                               3-14    3, 4-diClPh                                                                             4- iBuOPh    3, 4, 5-triMeOPh                               3-15    3, 4-diClPh                                                                             4-MePh       3, 4, 5-triMeOPh                               3-16    3, 4-diClPh                                                                             4- iBuOPh    3, 4, 5-triMeOPh                               3-17    Ph        3, 4-diMeOPh 3, 4-diMeOPh                                   3-18    3-ClPh    3, 4-diMeOPh 3, 4-diMeOPh                                   3-19    3-TfmPh   3, 4-diMeOPh 3, 4-diMeOPh                                   3-20    3-MePh    3, 4-diMeOPh 3, 4-diMeOPh                                   3-21    4-MeOPh   3, 4-diClPh  3, 4-dimeOPh                                   3-22    3-MeOPh   3, 4-diMePh  3, 4-diMeOPh                                   3-23    3-ClPh    3-ClPh       3, 4-diMeOPh                                   3-24    3-MePh    3-MePh       3, 4-diMeOPh                                   3-25    3-ClPh    4-PrOPh      3, 4-diMeOPh                                   3-26    3-ClPh    4- iBuOPh    3, 4-diMeOPh                                   3-27    3-MePh    4-PrOPh      3, 4-diMeOPh                                   3-28    3-MePh    4- iBuOPh    3, 4-diMeOPh                                   3-29    3, 4-diClPh                                                                             4-PrOPh      3, 4-diMeOPh                                   3-30    3, 4-diClPh                                                                             4- iBuOPh    3, 4-diMeOPh                                   3-31    3, 4-diClPh                                                                             4-MePh       3, 4-diMeOPh                                   3-32    3, 4-diClPh                                                                             4- iBuOPh    3, 4-diMeOPh                                   3-33    Ph        3, 4-diMeOPh 4-MeOPh                                        3-34    3-ClPh    3, 4-diMeOPh 4-MeOPh                                        3-35    3-TfmPh   3, 4-diMeOPh 4-MeOPh                                        3-36    3-MePh    3, 4-diMeOPh 4-MeOPh                                        3-37    4-MeOPh   3, 4-diClPh  4-MeOPh                                        3-38    4-MeOPh   3, 4-diMePh  4-MeOPh                                        3-39    3-ClPh    3-ClPh       4-MeOPh                                        3-40    3-MePh    3-MePh       4-MeOPh                                        3-41    3-ClPh    4-PrOPh      4-MeOPh                                        3-42    3-ClPh    4- iBuOPh    4-MeOPh                                        3-43    3-MePh    4-PrOPh      4-MeOPh                                        3-44    3-MePh    4- iBuOPh    4-MeOPh                                        3-45    3, 4-diClPh                                                                             4-PrOPh      4-MeOPh                                        3-46    3, 4-diClPh                                                                             4- iBuOPh    4-MeOPh                                        3-47    3, 4-diClPh                                                                             4-MePh       4-MeOPh                                        3-48    3, 4-diClPh                                                                             4- iBuOPh    4-MeOPh                                        3-49    Ph        3-MeO-4-PrOPh                                                                              3, 4, 5-triMeOPh                               3-50    Ph        3, 4-diPrOPh 3, 4, 5-triMeOPh                               3-51    Ph        3-PrO-4-MeOPh                                                                              3, 4, 5-triMeOPh                               3-52    3-ClPh    3-MeO-4-PrOPh                                                                              3, 4, 5-triMeOPh                               3-53    3-ClPh    3-PrO-4-MeOPh                                                                              3, 4, 5-triMeOPh                               3-54    3-ClPh    3, 4-diPrOPh 3, 4, 5-triMeOPh                               3-55    3-ClPh    3-MeOPh      3, 4, 5-triMeOPh                               3-56    3-MePh    3-MeO-4-PrOPh                                                                              3, 4, 5-triMeOPh                               3-57    3-MePh    3-PrO-4-MeOPh                                                                              3, 4, 5-triMeOPh                               3-58    3-MePh    3, 4-diPrOPh 3, 4, 5-triMeOPh                               3-59    3-TfmPh   3-MeO-4-PrOPh                                                                              3, 4, 5-triMeOPh                               3-60    3-TfmPh   3-PrO-4-MeOPh                                                                              3, 4, 5-triMeOPh                               3-61    3-TfmPh   3, 4-diPrOPh 3, 4, 5-triMeOPh                               3-62    3-BrPh    3-MeO-4-PrOPh                                                                              3, 4, 5-triMeOPh                               3-63    3-BrPh    3-PrO-4-MeOPh                                                                              3, 4, 5-triMeOPh                               3-64    3-BrPh    3, 4-diPrOPh 3, 4, 5-triMeOPh                               3-65    3-BrPh    3-MeOPh      3, 4, 5-triMeOPh                               3-66    3-BrPh    3-PrOPh      3, 4, 5-triMeOPh                               3-67    3-BrPh    4-MeOPh      3, 4, 5-triMeOPh                               3-68    3-BrPh    4-EtOPh      3, 4, 5-triMeOPh                               3-69    3-BrPh    4-PrOPh      3, 4, 5-triMeOPh                               3-70    3-BrPh    4-BuOPh      3, 4, 5-triMeOPh                               3-71    3-TfmPh   3-MeOPh      3, 4, 5-triMeOPh                               3-72    3-TfmPh   4-MeOPh      3, 4, 5-triMeOPh                               3-73    3-TfmPh   3-PrOPh      3, 4, 5-triMeOPh                               3-74    3-TfmPh   4-PrOPh      3, 4, 5-triMeOPh                               3-75    3-FPh     3-MeOPh      3, 4, 5-triMeOPh                               3-76    3-FPh     4-MeOPh      3, 4, 5-triMeOPh                               3-77    3-FPh     3-PrOPh      3, 4, 5-triMeOPh                               3-78    3-FPh     4-PrOPh      3, 4, 5-triMeOPh                               3-79    3, 5-diClPh                                                                             3-MeOPh      3, 4, 5-triMeOPh                               3-80    3, 5-diClPh                                                                             4-MeOPh      3, 4, 5-triMeOPh                               3-81    3, 5-diClPh                                                                             3-PrOPh      3, 4, 5-triMeOPh                               3-82    3, 5-diClPh                                                                             4-PrOPh      3, 4, 5-triMeOPh                               3-83    3-ClPh    4-CH.sub.3 O--Ph                                                                           3, 4, 5-triCH.sub.3 OPh                        3-84    2, 3-diClPh                                                                             4-CH.sub.3 O--Ph                                                                           3, 4, 5-triCH.sub.3 OPh                        3-85    2, 4-diClPh                                                                             4-CH.sub.3 O--Ph                                                                           3, 4, 5-triCH.sub.3 OPh                        3-86    2, 5-diClPh                                                                             4-CH.sub.3 O--Ph                                                                           3, 4, 5-triCH.sub.3 OPh                        3-87    2, 6-diClPh                                                                             4-CH.sub.3 O--Ph                                                                           3, 4, 5-triCH.sub.3 OPh                        3-88    3, 6-diClPh                                                                             4-CH.sub.3 O--Ph                                                                           3, 4, 5-triCH.sub.3 OPh                        ______________________________________                                    

Of the compounds listed above, the preferred compounds are CompoundsNos. 1-1, 1-2, 1-3, 1-4, 1-6, 1-14, 1-16, 1-17, 1-18, 1-19, 1-20, 1-25,1-26, 1-28, 1-29, 1-30, 1-41, 1-45, 1-46, 1-53, 1-76, 1-83, 1-91, 1-116,1-117, 1-118, 1-120, 1-129, 1-130, 1-133, 1-134, 1-141, 1-154, 1-155,1-207, 1-220, 1-298, 1-300, 1-313, 1-325, 1-327, 1-342, 1-343, 1-388,1-411, 1-412, 1-419, 1-420, 1-424, 1-425, 1-426, 1-431, 1-433, 1-441,1-445, 1-452, 1-453, 1-454, 1-455, 1-456, 1-457, 1-458, 1-459, 1-460,1-461, 1-462, 1-463, 1-466, 1-467, 1-468, 1-469, 1-470, 1-471, 1-472,1-473, 1-474, 1-475, 1-476, 1-477, 1-478, 1-479, 1-480, 1-481, 1-482,1-483, 1-484, 1-485, 1-486, 1-487, 1-488, 1-489, 1-490, 1-491, 1-492,1-496, 1-498, 1-501, 1-505, 1-507, 1-510, 1-511, 1-512, 1-513, 1-514,1-515, 1-516, 1-517, 1-518, 1-519, 1-520, 1-521, 1-522, 1-523, 1-524,1-525, 1-528, 1-529, 1-530, 1-531, 1-536, 1-537, 1-539, 1-541, 1-546,1-551, 1-552, 1-553, 1-556, 1-557, 1-558, 1-559, 1-560, 1-561, 1-562,1-563, 1-564, 1-565, 1-566, 1-567, 1-568, 1-569, 1-570, 1-571, 1-572,1-573, 1-574, 1-580, 1-581, 1-582, 1-583, 1-584, 1-585, 1-586, 1-587,1-588, 1-589, 1-590, 1-591, 1-592, 1-593, 1-594, 1-595, 1-596, 1-598,1-601, 1-602, 1-603, 1-604, 1-605, 1-606, 1-607, 1-608, 1-609, 1-610,1-611, 1-612, 1-616, 1-621, 1-622, 1-623, 1-624, 1-625, 1-626, 1-627,1-628, 1-629, 1-630, 1-631, 1-632, 1-633, 1-634, 1-635, 1-636, 1-637,1-638, 1-639, 1-640, 1-641, 1-642, 1-643, 1-644, 1-645, 1-646, 1-647,1-649, 1-650, 1-651, 1-652, 1-655, 1-659, 1-660, 1-661, 1-662, 1-663,1-664, 1-665, 1-666, 1-667, 1-668, 1-669, 1-670, 1-671, 1-672, 1-673,1-674, 1-675, 1-676, 1-677, 1-678, 1-679, 1-680, 1-681, 1-682, 1-683,1-684, 1-685, 1-686, 1-687, 1-688, 1-689, 1-690, 1-691, 1-692, 1-693,1-694, 1-695, 1-696, 1-697, 1-698, 1-699, 1-700, 1-701, 1-702, 1-703,1-704, 1-705, 1-706, 1-707, 1-708, 1-709, 1-710, 1-711, 1-712, 1-713,1-714, 1-715, 1-716, 1-717, 1-718, 1-719, 1-720, 1-721, 1-722, 1-723,1-724, 1-725, 1-726, 1-727, 1-728, 1-729, 1-730, 1-731, 1-732, 1-733,1-734, 1-735, 1-736, 1-737, 1-738, 1-739, 1-740, 1-741, 1-742, 1-743,1-744, 1-745, 1-746, 1-747, 1-748, 1-749, 1-750, 1-751, 1-752, 1-753,1-754, 1-755, 1-756, 1-757, 1-758, 1-759, 1-760, 1-761, 1-762, 1-763,1-764, 1-766, 1-771, 1-772, 1-773, 1-774, 1-777, 1-778, 1-779, 1-780,1-781, 1-782, 1-783, 1-784, 1-785, 1-787, 1-788, 1-789, 1-790, 1-799,1-801, 1-803, 1-805, 1-807, 1-809, 1-810, 1-813, 1-815, 1-817, 1-820,1-821, 1-823, 1-825, 1-832, 1-833, 1-845, 1-846, 1-850, 1-851, 1-858,1-859, 1-860, 1-862, 1-863, 1-866, 1-867, 1-871, 1-872, 1-873, 1-874,1-875, 1-876 2-1, 2-7, 2-8, 2-9, 2-15, 2-16, 2-19, 2-21, 2-23, 2-24,2-25, 2-29, 2-30, 2-31, 2-32, 2-35, 2-37, 2-41, 2-44, 2-45, 2-46, 2-47,2-51, 2-53, 2-57, 2-59, 2-62, 2-63, 2-66, 2-67, 2-68, 2-70, 2-72, 2-74,2-75, 2-77, 2-78, 2-80, 2-83, 2-84, 2-85, 2-86, 2-87, 2-88, 2-89, 2-90,2-91, 2-92, 2-93, 2-94, 2-101, 2-102, 2-103, 2-104, 2-107, 2-108, 2-109,2-110, 2-112, 2-163, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-11,3-13, 3-18, 3-19, 3-23, 3-25, 3-29, 3-34, 3-35, 3-37, 3-49, 3-50, 3-51,3-52, 3-54, 3-56, 3-58, 3-59, 3-61, 3-62, 3-64, 3-67 and 3-68.

The more preferred compounds are Compounds Nos. 1-28, 1-53, 1-419,1-424, 1-426, 1-431, 1-441, 1-445, 1-453, 1-454, 1-455, 1-456, 1-461,1-462, 1-463, 1-464, 1-467, 1-468, 1-469, 1-470, 1-472, 1-475, 1-476,1-478, 1-480, 1-482, 1-483, 1-484, 1-486, 1-510, 1-512, 1-513, 1-514,1-515, 1-517, 1-519, 1-521, 1-524, 1-529, 1-531, 1-541, 1-546, 1-558,1-560, 1-568, 1-570, 1-574, 1-581, 1-582, 1-585, 1-587, 1-590, 1-592,1-594, 1-598, 1-603, 1-606, 1-609, 1-622, 1-627, 1-628, 1-631, 1-632,1-637, 1-660, 1-668, 1-670, 1-671, 1-675, 1-679, 1-680, 1-681, 1-684,1-685, 1-693, 1-694, 1-702, 1-703, 1-707, 1-710, 1-713, 1-714, 1-717,1-718, 1-719, 1-727, 1-728, 1-730, 1-731, 1-733, 1-737, 1-740, 1-743,1-746, 1-752, 1-758, 1-759, 1-772, 1-773, 1-777, 1-778, 1-784, 1-799,1-803, 1-805, 1-813, 1-815, 1-845, 1-858, 1-859, 1-866, 1-867, 1-872,1-873, 1-874, 1-875, 1-876, 3-2, 3-3, 3-5, 3-49, 3-50, 3-52, 3-54, 3-56and 3-59.

The most preferred compounds are:

1-28.1-[3-(3,4-Dimethoxyphenyl)-3-phenylacryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-419.1-[3,3-Bis(3-chlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-424.1-[3,3-Bis(3-methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-426.1-[3,3-Bis(3-trifluoromethylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-453.1-[3-(2-Chlorophenyl)-3-(3-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-454.1-[3-(2-Chlorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-455.1-[3-(2-Chlorophenyl)-3-(3-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-467.1-[3-(3-Chlorophenyl)-3-(3-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-468.1-[3-(3-Chlorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-469.1-[3-(3-Chlorophenyl)-3-(3-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-470.1-[3-(3-Chlorophenyl)-3-(4-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-482.1-[3-(3-Chlorophenyl)-3-(3,4-dimethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-483.1-[3-(3-Chlorophenyl)-3-(4-methoxy-3-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-484.1-[3-(3-Chlorophenyl)-3-(3,4-dipropoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-513.1-[3-(3,4-Dichlorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-515.1-[3-(3,4-Dichlorophenyl)-3-(4-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-557.1-[3-(3-Trifluoromethylphenyl)-3-(3-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-559.1-[3-(3-Trifluoromethylphenyl)-3-(3-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-574.1-[3-(3-Trifluoromethylphenyl)-3-(3,4-dimethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-590.1-[3-(3-Methylphenyl)-3-(3,4-dimethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-594.1-[3-(3-Methylphenyl)-3-(4-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-603.1-[3-(3-Methoxy-4-propoxyphenyl)-3-phenylacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-606.1-[3-(3,4-Dipropoxyphenyl)-3-phenylacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-622.1-[3-(4-Ethoxy-3-methoxyphenyl)-3-phenylacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-627.1-[3-(4-Butoxy-3-methoxyphenyl)-3-phenylacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-685.1-[3-(3-Methoxy-4-propoxyphenyl)-3-(3-trifluoromethylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-710.1-[3-(3-Methoxy-4-propoxyphenyl)-3-(3-methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-740.1-[3-(3-Chlorophenyl)-3-(3-methoxy-4-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-743.1-[3-(3-Chlorophenyl)-3-(4-ethoxy-3-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine;

1-799.1-[3-(3,5-Dichlorophenyl)-3-(4-ethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

1-803.1-[3-(2,5-Dichlorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

1-805.1-[3-(2,5-Dichlorophenyl)-3-(4-ethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

1-858.1-[3-(3,5-Difluorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

1-859.1-[3-(3,5-Difluorophenyl)-3-(4-ethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

1-872.1-[3-(3-Fluorophenyl)-3-(4-ethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

1-873.1-[3-(3-Chloro-5-methylphenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazineand

1-874.1-[3-(3-Chloro-5-methylphenyl)-3-(4-ethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine.

The N-acryloylpiperazine derivatives of the present invention can beprepared by the procedures described below.

Where it is desired to prepare any compound of the present inventionwhich has a thiocarbonyl group in its molecule, it can, in general, beprepared by any of the reactions described below from the correspondingstarting material also having a thiocarbonyl group in its molecule.Alternatively, it can also be prepared by first synthesizing thecorresponding compound having a carbonyl group in its molecule and thenreacting the carbonyl compound with a reagent which converts thecarbonyl group into a thiocarbonyl group, such as Lawesson's Reagentwhich consists mainly of[2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide]by conventional means. If the compound has two carbonyl groups in itsmolecule, selective conversion of these two carbonyl groups into eithertwo thiocarbonyl groups or one thiocarbonyl group is possible byselection of the reaction conditions.

In general terms, the compounds of the present invention may be preparedby reacting a compound of formula (II): ##STR6## with a compound offormula (III):

    Z.sup.2 --B'--R.sup.4                                      (III)

(in which one of Z¹ and Z² represents a group represented by Y and theother represents a group of formula --A--H; Y represents a nucleophilicleaving group; and R¹, R², R³, R⁴, X, A and B' are as defined above).

Examples of nucleophilic leaving groups which may be represented by Yinclude: halogen atoms, such as the chloride, bromide or iodine atoms;azide groups; and lower alkoxycarbonyloxy groups in which the alkoxypart has from 1 to 4, preferably 1 to 2, carbon atoms, such as themethoxycarbonyloxy and ethoxycarbonyloxy groups.

More specifically, examples of preferred methods of preparing thecompounds of the present invention are as illustrated in the followingMethods A and B. ##STR7##

In these formulae, R¹, R², R³, R⁴, X, A, B' and Y are as defined above.

In Step A-1 the carboxylic acid derivative of formula (IV) is convertedto an activated derivative thereof of formula (V).

This activation may be carried out using conventional techniques, whichwill, of course, depend on the nature of the active derivative offormula (V) to be prepared. For example, where it is desired to preparean acyl halide compound, a phosphorus chloride (such as phosphoruspentachloride or phosphorus trichloride) or a sulfuric acid derivative(such as thionyl chloride) is reacted with the carboxylic acid offormula (IV). Where it is desired to prepare an acyl azide compound, anazidation reagent, such as diphenylphosphorylazide (DPPA), is employed,together with an organic base. Where it is desired to prepare a loweralkoxycarbonyloxy compound, a lower alkyl halocarboxylate, such as ethylchloroformate, is employed, together with an organic base.

Where an organic base is employed in this reaction, there is noparticular limitation on its nature, and any base commonly used for thistype of reaction may equally be employed here. Examples of suitableorganic bases include: trialkylamines, such as triethylamine anddiisopropylethylamine; and cyclic amines, such as N-methylmorpholine,pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline,1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

In Step A-2 the compound of formula (I) of the present invention isprepared by reacting the activated carboxylic acid derivative of formula(V) with the compound of formula (VI). This reaction may take place inthe presence or absence of a base and preferably in a solvent.

When the activated carboxylic acid derivative of formula (V) is an acylhalide, a base is preferably employed. There is no particularrestriction on the nature of the base employed for this reaction, andany base commonly employed in reactions of this type may equally beemployed here. If an inorganic base [for example: an alkali metalcarbonate (such as sodium carbonate or potassium carbonate); an alkalimetal bicarbonate (such as sodium bicarbonate or potassium bicarbonate);an alkali metal hydride (such as lithium hydride, sodium hydride orpotassium hydride); or an alkali metal hydroxide (such as sodiumhydroxide, potassium hydroxide or barium hydroxide)] is employed, thepreferred solvent is: an ether, such as diethyl ether, tetrahydrofuran,dioxane or dimethoxyethane; an amide, such as dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; a sulfoxide such asdimethyl sulfoxide; a nitrile such as acetonitrile; water; or a mixtureof water with any one or more of the organic solvents mentioned above.If an organic base [such as triethylamine, diisopropylethylamine,N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,N,N-dimethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene,1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU)] is employed, the preferred solvent is: an aromatic hydrocarbon,such as benzene, toluene or xylene; an ether, such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane; or a halogenatedhydrocarbon, especially a halogenated aliphatic hydrocarbon, such asmethylene chloride or chloroform.

When the activated carboxylic acid derivative of formula (V) is an acylazide compound or a lower alkoxycarbonyloxy compound, the organic basementioned above is not always necessary, because the reaction willproceed even in the absence of the base. However, a base may beemployed, if desired. There is no particular restriction on the natureof the solvent to be employed, provided that it has no adverse effect onthe reaction or on the reagents involved. Examples of suitable solventsinclude: aromatic hydrocarbons, such as benzene, toluene or xylene;halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons,such as methylene chloride or chloroform; ethers, such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane; amides, such asdimethylformamide, dimethylacetamide or hexamethylphosphoric triamide;sulfoxides, such as dimethyl sulfoxide; and nitriles, such asacetonitrile.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature from 0° C. to 50° C., preferably at room temperature. Thetime required for the reaction may also vary widely, depending on manyfactors, notably the reaction temperature and the nature of thereagents. However, provided that the reaction is effected under thepreferred conditions outlined above, a period of from 15 minutes to 1day will usually suffice.

Certain of the compounds of formula (VI) used in Step A-2 are known {forexample, 1-(3,4,5-trimethoxybenzoyl)piperazine, L. Toldy et al., Acta.Chim. Acad. Sci. Hung., 49 (3), 265-285 (1966), and1-[3,4,5-trimethoxy(thiobenzoyl)]piperazine, C. Farina et al., Eur. Med.Chem. Chimica Therapeutica, 14 (1), 27-31 (1979)}. Otherwise, they canbe prepared by the reaction of the compound of formula (VII) with thecompound of formula (IX) both of which will be described later,according to Method B. ##STR8##

In these formulae, R¹, R², R³, R⁴, Y, X, A and B' are as defined above.

In Step B-1, a compound of formula (VIII) is prepared by: first,reacting the activated carboxylic acid derivative of formula (V)(prepared as described in Step A-1) with the compound of formula (VII);and then removing the formyl group which is a substituent on thenitrogen atom of the piperazine or homopiperazine ring "A". The reactionin the first part of this Step is essentially the same as and may becarried out under the same conditions as that of Step A-2, and using thesame reagents as described therein.

The removal of the formyl group in the latter half of the Step iscarried out by treating the formyl compound prepared in the first partof the Step with a base in the presence of a solvent. There is noparticular restriction on the nature of the base employed, provided thatit does not affect any other part of the compounds in the reactionmixture. The reaction is preferably carried out using as the base: ametal alkoxide, such as sodium methoxide; an alkali metal carbonate,such as sodium carbonate or potassium carbonate; an alkali metalhydroxide, such as sodium hydroxide or potassium hydroxide; aqueousammonia or concentrated methanolic ammonia. There is no particularrestriction on the nature of the solvent employed, provided that it hasno adverse effect on the reagents and that it is capable of dissolvingthe reagents, at least to some extent. Examples of suitable solventsinclude any of those commonly used for hydrolytic reactions, forexample, an organic solvent, such as: an alcohol, e.g. methanol, ethanolor propanol; or an ether, such as tetrahydrofuran or dioxane; also wateror a mixture of water with any one or more of the organic solventsmentioned above may be used.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, in order to avoid side reactions, we find it convenient tocarry out the reaction at a temperature in the range of from 0° C. to150° C., preferably at room temperature, although the exact preferredtemperature may vary depending upon the starting materials, the base andthe reaction solvent. The time required for the reaction may likewisevary widely, depending on many factors, notably the reaction temperatureand the nature of the reagents. However, in most cases, a period of from1 to 24 hours will normally suffice.

In Step B-2, a compound of formula (I) is prepared by reacting acompound of formula (VIII) with a compound of formula (IX) in thepresence of a base and in a solvent.

Where B' represents any group other than a lower alkylene group, thereaction is essentially the same as and may be carried out according tothe procedure described in Step A-2. When B' represents a lower alkylenegroup, the base is preferably an alkali metal hydride, such as lithiumhydride, sodium hydride or potassium hydride. There is no particularrestriction on the nature of the solvent employed, provided that it doesnot hinder the reaction and that it can dissolve the starting materialsat least to some degree. Preferred solvents are: ethers, such as diethylether, tetrahydrofuran, dioxane or dimethoxyethane; and amides, such asdimethylformamide, dimethylacetamide or hexamethylphosphoric triamide.

After completion of the reaction, the desired compound from everyreaction mentioned above can be collected from the reaction mixture byconventional means. For example, it can be obtained by adding awater-immiscible organic solvent to the reaction mixture, followed bywashing with water, and then distilling off the solvent. The compoundthus obtained can, if necessary, be further purified by conventionalmeans, such as recrystallization, reprecipitation or the variouschromatography techniques, notably column chromatography.

The carboxylic acid derivative of formula (IV), in which X represents anoxygen atom, that is to say the compound of formula (XIII), which is oneof the starting materials employed in the process of the presentinvention may be prepared as illustrated in the following Method C:##STR9##

In these formulae, R¹, R² and R³ are as defined above, R⁶ represents aC₁ -C₆ alkyl group, and R⁷ represents a C₁ -C₆ alkyl group or an arylgroup which may optionally be substituted, as defined above in relationto R⁵.

In Step C-1, a compound of formula (XII) is prepared by reacting aketone compound of formula (X) with Horner's reagent, the compound offormula (XI). This reagent can be prepared, for example, by the wellknown Arbuzov reaction. Step C-1 takes place in the presence of a baseand in a solvent.

There is no particular restriction on the nature of the base employed,provided that it has no adverse effect on other parts of the molecule.Examples of suitable bases include: inorganic bases, such as alkalimetal hydrides (e.g. lithium hydride, sodium hydride or potassiumhydride) and alkali metal hydroxides (e.g. sodium hydroxide, potassiumhydroxide or barium hydroxide); organic bases, such as1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and organic metal bases, suchas butyllithium and lithium diisopropylamide.

There is no particular restriction on the nature of the solventemployed, provided that it does not hinder the reaction and that it candissolve the starting materials, at least to some degree. Examples ofpreferred solvents include: aromatic hydrocarbons, such as benzene,toluene or xylene; ethers, such as diethyl ether, tetrahydrofuran,dioxane or dimethoxyethane; amides, such as dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; and sulfoxides, suchas dimethyl sulfoxide.

In Step C-2, the starting material of formula (XIII) used in the presentinvention is prepared by removing the group R⁶, which is thecarboxy-protecting group in the compound of formula (XII).

Removal of the protecting group may be carried out by any known reactionfor removing groups of this type, for example by treatment with an acidor a base. Examples of suitable acids include hydrochloric acid,sulfuric acid, phosphoric acid and hydrobromic acid. There is noparticular restriction on the nature of the base, provided that it doesnot affect other parts of the compounds in the reaction mixture;however, we prefer to use: alkali metal carbonates, such as sodiumcarbonate or potassium carbonate; alkali metal hydroxides, such assodium hydroxide or potassium hydroxide; or concentrated methanolicammonia. There is likewise no particular restriction on the nature ofthe solvent, and any solvent commonly used for hydrolytic reactions mayequally be used here, provided that it has no adverse effect on any ofthe reagents and that it is capable of dissolving the reagents, at leastto some extent. Examples include: water and mixtures of water with anorganic solvent, for example: an alcohol such as methanol, ethanol orpropanol; or an ether, such as tetrahydrofuran or dioxane.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention,although the preferred temperatures may vary depending on the startingmaterials and the base employed. In general, we find it convenient tocarry out the reaction at a temperature in the range of from 0° C. to150° C. The time required for the reaction may likewise vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents. However, in most cases, a period of from 1 to 10hours will normally suffice.

When the substituents R¹ and R² are different, the product will normallybe obtained as a mixture of its geometrical isomers. By usingchromatography or similar techniques, as is well known, in each of StepsC-1 and C-2, the (E)-form and (Z)-form can be obtained separately, ifdesired.

In general, the compounds of formula (X), which are starting materialsin this reaction, are well known. However, where they are not, they canbe prepared, for example, by reacting a compound of formula R¹ --CHO (inwhich R¹ is as defined above) with a compound of formula R² --MgZ (inwhich R² is as defined above and Z represents a halogen atom) or with acompound of formula R² --Li (in which R² is as defined above), or byreacting a compound of formula R² --CHO (in which R² is as definedabove) with a compound of formula R¹ --MgZ (in which R¹ and Z are asdefined above) or with a compound of formula R¹ --Li (in which R¹ is asdefined above), followed by oxidizing the alcohol compound thus formedto its corresponding carbonyl compound by conventional means.

Further, by application of the famous Friedel-Crafts reaction, thesecompounds of formula (X) can be also prepared by reacting a compound offormula R¹ H (in which R¹ is as defined above) with a compound offormula R² --COZ (in which R² and Z are as defined above), or byreacting a compound of formula R² H (in which R² is as defined above)with a compound of formula R¹ --COZ (in which R¹ and Z are as definedabove).

The following Method D provides an alternative method of preparing acompound of formula (XIII), in which R³ does not represent a hydrogenatom, that is to say a compound of formula (XVI). ##STR10##

In the above formulae, R¹, R² and R⁶ are as defined above; R^(3')represents any of the groups in the definition of R³ other than ahydrogen atom; and R' represents a carboxy-protecting group, which mayor may not be the same as the group represented by R⁶.

In this reaction scheme, the starting material of formula (XVI) of thepresent invention is prepared by treating a compound of formula (XIV)with a base in the presence of solvent at -78° C. -0° C. to yield ananion of formula (XIV') (Step D-1), which is then reacted, in Step D-2,with a compound of formula (X) (see Method C); this is then treated, inStep D-3, with a dehydrating agent, such as an acid or phosphorusoxychloride, in the presence or absence of a solvent, and then the estergroup is hydrolized by conventional means.

In Steps D-1 and D-2, there is no particular restriction on the natureof the solvent to be employed, provided that it has no adverse effect onthe reaction or on the reagents involved. Examples of suitable solventsinclude: aliphatic hydrocarbons, such as hexane and heptane; aromatichydrocarbons, such as benzene, toluene and xylene; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and diethylene glycol dimethyl ether; amides, such asformamide, dimethylformamide, dimethylacetamide and hexamethylphosphorictriamide; and sulfoxides, such as dimethyl sulfoxide and sulfolane.

There is no particular restriction on the nature of the base employedfor the reaction of Step D-1, and any base commonly employed inreactions of this type may equally be employed here. Examples ofsuitable bases include: inorganic bases, such as alkali metal hydrides(e.g. lithium hydride, sodium hydride or potassium hydride); organicbases, such as 1,5-diazabicyclo[4.3.0]nona-5-ene,1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU); and organic metal bases such as butyllithium and lithiumdiisopropylamide.

In Step D-2, which is preferably carried out without intermediateisolation of the anion of formula (XIV') produced in Step D-1, the anionis reacted with a compound of formula (X), to give a compound of formula(XV). The reaction is preferably carried out in the same reaction mediumand under the same conditions as Step D-1.

Step D-3 consists of the reaction of the resulting compound of formula(XV) with a dehydrating agent, to give the desired compound of formula(XVI). This reaction may take place in the presence or absence of asolvent. There is no particular restriction on the nature of thesolvent, where it is employed, provided that it has no adverse effect onthe reaction or on the reagents involved. Examples of suitable solventsinclude: aliphatic hydrocarbons, such as hexane and heptane; aromatichydrocarbons, such as benzene, toluene and xylene; halogenatedhydrocarbons, especially halogenated aliphatic hydrocarbons, such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene and the dichlorobenzenes; esters, such as ethyl formate,ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols,such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol,t-butanol, isoamyl alcohol, diethylene glycol, glycerine, octanol,cyclohexanol and methylcellosolve; ketones, such as acetone, methylethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone;nitro compounds, such as nitroethane and nitrobenzene; nitriles, such asacetonitrile and isobutyronitrile; amides, such as formamide,dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide;and sulfoxides, such as dimethyl sulfoxide and sulfolane.

There is likewise no particular restriction on the nature of the acidemployed for this reaction, and any acid commonly employed as a protondonor and classified as a Brensted acid may equally be employed here.Examples of suitable acids include: organic acids, such asp-toluenesulfonic acid or camphorsulfonic acid; and inorganic acids,such as hydrochloric acid or sulfuric acid.

When an phosphorus oxychloride is employed as the dehydrating reagent,an aprotic solvent should be used. Preferred such solvents include thealiphatic hydrocarbons, aromatic hydrocarbons or halogenatedhydrocarbons listed above.

When the substituents R¹ and R² are different, the product will normallybe obtained as a mixture of its geometric isomers. By usingchromatography or similar techniques, as is well known, the z-form andthe E-form can be obtained separately, if desired.

Alternatively, the starting material of formula (XVI) may be prepared byreacting the compound of formula (X) with a compound of formula:##STR11## using activated zinc powder in the presence of a solventaccording to the same Reformatsky reaction as is reported by Kametani etal. [Yakugakuzassi, 88, 911 (1968)], followed by dehydration andhydrolysis in a similar manner to that described above.

There is no particular restriction on the nature of the solvent to beemployed in the Reformatsky reaction, provided that it has no adverseeffect on the reaction or on the reagents involved. Examples of suitablesolvents include: aliphatic hydrocarbons, such as hexane or heptane; andaromatic hydrocarbons, such as benzene, toluene or xylene, preferablyaromatic hydrocarbons.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature from 0° C. to the boiling point of the reaction medium,preferably at a temperature from 80° C. to 100° C. The time required forthe reaction may also vary widely, depending on many factors, notablythe reaction temperature, the nature of the reagents, and the nature ofthe solvent. However, provided that the reaction is effected under thepreferred conditions outlined above, a period of from 1 to 24 hours,preferably from 2 to 6 hours, will usually suffice.

An alternative method of preparing the compound of formula (XIII) inwhich R² represents a group --R⁵, as defined above, that is to say acompound of formula (XVIII), is shown in Method E: ##STR12##

In these formulae, R¹, R³ and R⁶ are as defined above, and R^(2')represents a group of formula --R⁵, as defined above for R².

In step E-1, the compound of formula (XVIII) is prepared by reacting thecompound of formula (XVII), according to Heck's reaction, with acompound of formula R^(2') --Y (in which R^(2') and Y are as definedabove) in the presence of a palladium salt, such as palladium acetate,in a solvent, and then removing the carboxy-protecting group, R⁶, asmentioned above.

There is no particular restriction on the nature of the solventemployed, provided that it does not hinder the reaction and that it candissolve the starting compounds, at least to some degree. Examples ofpreferred solvents include: nitriles, such as acetonitrile; aromatichydrocarbons, such as benzene, toluene and xylene; esters, such as ethylacetate and propyl acetate; ethers, such as diethyl ether,tetrahydrofuran, dioxane and dimethoxyethane; amides, such asdimethylformamide, dimethylacetamide and hexamethylphosphoric triamide;and sulfoxides, such as dimethyl sulfoxide.

The compound of formula (XVII) used as the starting material can beprepared from a compound of formula R¹ --CHO (in which R¹ is as definedabove), using the techniques of Method C or Method D.

An alternative method of preparing a compound of formula (XII) in whichR³ represents a hydrogen atom, that is to say a compound of formula(XXI), is shown in Method F: ##STR13##

In these formulae, R¹, R², R⁶ and Z are as defined above.

In Step F-1, the compound of formula (XXI) is prepared from the compoundof formula (XX).

When R² is R^(2') (as defined above), the compound of formula (XXI) isprepared by reacting the compound of formula (XX) with a compound offormula R^(2') --MgZ (in which R^(2') and Z are as defined above) in thepresence of a divalent nickel complex such asbis(diphenylphosphino)ethane nickel (II) chloride in a solvent, followedby removing the carboxy-protecting group, R⁶, by the procedure mentionedabove.

There is no particular restriction on the nature of the solventemployed, provided that it does not hinder the reaction and that it candissolve the starting compounds, at least to some degree. Examples ofpreferred solvents include: aromatic hydrocarbons, such as benzene,toluene or xylene; and ethers, such as diethyl ether, tetrahydrofuran,dioxane or dimethoxyethane.

When R² represents any group other than R^(2'), the compound of formula(XXI) may be prepared by reacting the compound of formula (XX) with acompound of formula R⁵ --CH═CH₂ (in which R⁵ is as defined above) orwith a compound of formula R⁵ --C═CH (in which R⁵ is as defined above)in the presence of a palladium complex such as bis(triphenylphosphine)palladium (II) chloride in a solvent, followed by removing thecarboxy-protecting group, R⁶.

In the first part of this reaction, the reaction may occasionally becarried out preferably in the presence of an organic base, such astriethylamine.

There is no particular restriction on the nature of the solvent employedin this reaction, provided that it does not hinder the reaction and thatit can dissolve the starting compounds, at least to some degree.Examples of preferred solvents include: aromatic hydrocarbons, such asbenzene, toluene and xylene; halogenated hydrocarbons, especiallyhalogenated aliphatic hydrocarbons, such as methylene chloride andchloroform; ethers, such as diethyl ether, tetrahydrofuran, dioxane anddimethoxyethane; amides, such as dimethylformamide, dimethylacetamideand hexamethylphosphoric triamide; and sulfoxides, such as dimethylsulfoxide.

The compound of formula (XX) used as the starting material in thisreaction can be prepared by the addition of a halogen atom, such as achlorine or bromine atom, to a compound of formula (XVII) wherein R³represents a hydrogen atom, followed by removing a hydrogen halide, suchas hydrogen bromide or hydrogen chloride, to form a triple bond, andthen followed by the addition of a hydrogen halide such as hydrogenbromide.

As will be demonstrated hereafter, the novel N-acryloylpiperazinederivatives of the present invention have an excellent PAF-antagonistactivity, and, moreover, have excellent stability on oraladministration. Accordingly, these derivatives are expected to be usefulfor the therapy and prophylaxis of various diseases and disorders inwhich PAF is thought to be implicated, such as endotoxin-induced shock,anaphylactic shock, nephritis, myocardial infarction, angina pectoris,asthma, psoriasis and gastric ulceration.

The compounds of the invention may be administered orally orparenterally, as required, and may, if desired, be formulated intoappropriate pharmaceutical preparations, the nature of which will dependupon the desired route of administration. For example, for oraladministration, the compounds may be formulated as tablets, capsules,granules, powders or syrups. For parenteral administration, they may beformulated as injectible solutions or suspensions or as suppositories.Although the preferred dose will vary, depending upon the nature of thedisorder, as well as upon the symptoms, age, condition and body weightof the patient and the route of administration, a preferred dose for anadult human patient would normally be expected to be from 0.2 to 50mg/kg body weight per day, and this could be administered in a singledose or in divided doses.

These preparations can be formulated using any conventional additivessuch as vehicles, binders, disintegrating agents, lubricants,stabilizers and corrigents, as is well known in the art.

The invention is further illustrated by the following non-limitingExamples. Preparation of certain of the starting materials employed inthese Examples is illustrated by the subsequent Preparations. Thebiological activities of certain of the compounds of the invention arethen illustrated in the subsequent Experiments, and these are followedby examples of Formulations of the invention.

EXAMPLE 1

1-(3,3-Diphenylacryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine

4.164 g of phosphorus pentachloride were added to 90 ml of a methylenechloride solution containing 4.485 g of 3,3-diphenylacrylic acid, whichhad previously been cooled at 0°-5° C. The reaction mixture was thenstirred for one hour at room temperature, after which the solvent wasdistilled off under reduced pressure. The resulting residue wasdissolved in 50 ml of toluene, and then the solvent was once againdistilled off under reduced pressure. This procedure comprisingdissolution and distillation was repeated once more.3,3-Diphenylacryloyl chloride was obtained as a white solid. This crudeproduct was immediately used in the next reaction.

0.840 g of sodium bicarbonate dissolved in 15 ml of water was added to30 ml of a tetrahydrofuran solution containing 1.401 g of1-(3,4,5-trimethoxybenzoyl)piperazine. 1.214 g of the3,3-diphenylacryloyl chloride obtained as described above were added tothe mixture, in one go, and the resulting mixture was stirred for 30minutes at room temperature. At the end of this time, 50 ml of methylenechloride were added to the reaction mixture, the organic phase and theaqueous phase were separated from each other, and the aqueous phase wereseparated from each other, and the aqueous phase was extracted withmethylene chloride. The methylene chloride phase and the methylenechloride extract were combined and washed with 10% w/v aqueoushydrochloric acid, with a 5% w/v aqueous solution of sodium bicarbonateand with a saturated aqueous solution of sodium chloride, in that order.The methylene chloride solution was dried over anhydrous sodium sulfate,and then the solvent was removed by distillation under reduced pressure.The oily residue (2.70 g) was purified by silica gel flashchromatography. Those fractions which were eluted with a 100:1 by volumemixture of methylene chloride and methanol were collected to afford2.150 g of the title compound as a white powder. Recrystallization ofthis from a mixture of ethyl acetate and hexane gave white needles,melting at 148°-150° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.65-3.80(8H, multiplet); 3.84 (6H, singlet); 3.85 (3H, singlet); 6.30 (1H,singlet); 6.52 (2H, singlet); 7.2-7.5 (10H, multiplet).

Mass spectrum (m/z): 486 (M⁺), 291 (M⁺ --C₁₀ H₁₁ O₄), 279 (M⁺ --C₁₅ H₁₁O), 207 (C₁₅ H₁₁ O), 195 (C₁₀ H₁₁ O₄).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1585.

Elemental analysis: Calculated for C₂₉ H₃₀ N₂ O₅ : C, 71.59%; H, 6.21%;N, 5.76%. Found: C, 71.54%; H, 6.44%; N, 5.71%.

EXAMPLE 2

1-[3,3-Bis(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Following a procedure similar to that described in Example 1, but using0.500 g of 3,3-bis(4-methoxyphenyl)acrylic acid, 0.362 g of the titlecompound was obtained as a powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.70-3.75(8H, multiplet); 3.82 (3H, singlet); 3.84 (3H, singlet); 3.85 (9H,singlet); 6.14 (1H, singlet); 6.54 (2H, singlet); 6.80-6.93 (4H,multiplet); 7.18-7.30 (4H, multiplet).

Mass spectrum (m/z): 546 (M⁺), 351 (M⁺ --C₁₀ H₁₁ O₄), 279 (M⁺ --C₁₇ H₁₅O₃), 267 (C₁₇ H₁₅ O₃), 195 (C₁₀ H₁₁ O₄).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1605, 1585.

EXAMPLE 3

1-[3,3-Bis(4-chlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Following a procedure similar to that described in Example 1, but using0.500 g of 3,3-bis(4-chlorophenyl)acrylic acid, 0.938 g of the titlecompound was obtained as a white powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.90-3.70(8H, multiplet); 3.86 (9H, singlet); 6.32 (1H, singlet); 6.56 (2H,singlet); 7.15-7.40 (8H, multiplet).

Mass spectrum (m/z): 554 (M⁺) 359 (M⁺ --C₁₀ H₁₁ O₄), 279 (M⁺ --C₁₅ H₉Cl₂ O), 275 (C₁₅ H₉ Cl₂ O); 195 (C₁₀ H₁₁ O₄).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1590.

EXAMPLE 4

1-[3,3-Bis(2-thienyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Following a procedure similar to that described in Example 1, but using0.500 g of 3,3-bis(2-thienyl)acrylic acid, 0.719 g of the title compoundwas obtained as a white powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.90-3.75(8H, multiplet); 3.85 (9H, singlet); 6.34 (1H, singlet); 6.57 (2H,singlet); 7.02 (1H, doublet of doublets, J=5.13 & 3.66 Hz); 7.08 (1H,doublet of doublets, J=5.13 & 3.66 Hz); 7.13 (1H, doublet of doublets,J=1.10 & 3.66 Hz); 7.26 (1H, doublet of doublets, J=1.10 & 3.66 Hz);7.32 (1H, doublet of doublets, J=5.13 & 1.10 Hz); 7.42 (1H, doublet ofdoublets, J=5.13 & 1.10 Hz).

Mass spectrum (m/z): 498 (M⁺), 303 (M⁺ --C₁₀ H₁₁ O₄), 279 (M⁺ --C₁₁ H₇OS₂), 219 (C₁₁ H₇ OS₂), 195 (C₁₀ H₁₁ O₄).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1620, 1585.

Elemental analysis: Calculated for C₂₅ H₂₆ N₂ O₅ S₂ : C, 60.22%; H,5.26%; N, 5.62%; S, 12.86%. Found: C, 60.34%; H, 5.43%; N, 5.59%; S,12.97%.

EXAMPLE 5

1-[(Z)-3-Phenyl-3-(2-thienyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazin

Following a procedure similar to that described in Example 1, but using0.480 g of (Z)-3-phenyl-3-(2-thienyl)acrylic acid (prepared as describedin Preparation 1, Isomer A, melting at 144°-147° C.), 0.703 g of thetitle compound was obtained as a white powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.70-3.75(8H, multiplet); 3.84 (3H, singlet); 3.85 (6H, singlet); 6.41 (1H,singlet); 6.53 (2H, singlet); 6.88 (1H, doublet of doublets, J=3.67 &1.10 Hz); 6.98 (1H, doublet of doublets, J=5.13 & 3.67 Hz); 7.30 (1H,doublet of doublets, J=5.13 & 1.10 Hz); 7.40 (5H, singlet-like).

Mass spectrum (m/z): 492 (M⁺), 297 (M⁺ --C₁₀ H₁₁ O₄), 279 (M⁺ --C₁₃ H₉OS), 213 (C₁₃ H₉ OS), 195 (C₁₀ H₁₁ O₄).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1620, 1585.

Elemental analysis: Calculated for C₂₇ H₂₈ N₂ O₅ S: C, 65.83%; H, 5.73%;N, 5.69%; S, 6.51%. Found: C, 65.68%; H, 5.97%; N, 5.79%; S, 6.51%.

EXAMPLE 6

1-[(E)-3-Phenyl-3-(4-pyridyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

1 ml of a methylene chloride solution containing 0.330 g ofdiphenylphosphoryl azide and then 0.280 g of1-(3,4,5-trimethoxybenzoyl)piperazine were added to 5 ml of a methylenechloride solution containing both 0.224 g of(E)-3-phenyl-3-(4-pyridyl)acrylic acid (prepared as described inPreparation 3) and 0.28 ml of triethylamine. The mixture was thenstirred for 4 hours at room temperature, after which the reactionsolution was diluted with 20 ml of methylene chloride. It was thenwashed with a 5% w/v aqueous solution of sodium bicarbonate, followed bya saturated aqueous solution of sodium chloride, and the organic phasewas dried over anhydrous sodium sulfate. The solvent was then removed bydistillation under reduced pressure, and the oily residue (0.686 g) waspurified by silica gel flash chromatography. 0.419 g of the titlecompound was obtained as a white powder from the fractions eluted withmixtures of methylene chloride and methanol ranging from 100:2 to 100:3by volume.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 3.05-3.70(8H, multiplet); 3.84 (9H, multiplet); 6.50 (1H, singlet); 6.58 (2H,singlet); 7.10-7.68 (7H, multiplet); 8.45-8.85 (2H, multiplet).

Mass spectrum (m/z): 487 (M⁺), 292 (M⁺ --C₁₀ H₁₁ O₄), 279 (M⁺ --C₁₄ H₁₀NO), 208 (C₁₄ H₁₀ NO), 195 (C₁₀ H₁₁ O₄).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630.

EXAMPLES 7 TO 56

The following compounds were synthesized from the appropriate startingmaterials prepared as described in the subsequent Preparations,following the general synthetic method given below.

General synthetic method:

0.793 g (2.88 mmole) of diphenylphosphoryl azide and then 0.449 g (1.60mmole) of N-(3,4,5-trimethoxybenzoyl)piperazine were added to 7 ml of amethylene chloride solution containing 1.60 mmole of the respective3,3-disubstituted-acrylic acid derivative (identified by the number ofthe Preparation shown in which it was prepared) and 0.67 ml (4.80 mmole)of triethylamine. The reaction mixture was then stirred for 3 hours atroom temperature, after which it was diluted with 20 ml of methylenechloride. The resulting solution was washed with a saturated aqueoussolution of sodium bicarbonate, with 10% w/v aqueous hydrochloric acidand with water, in that order, and the solution was then dried overanhydrous sodium sulfate. The solvent was distilled off, and the residuewas subjected to moderate pressure liquid chromatography using two LobarB columns connected in series. Elution with ethyl acetate removed theless polar impurities from the residue. Next, elution with mixtures ofmethylene chloride and methanol ranging from 100:1 to 100:2 by volumegave a desiredN-(3,3-disubstituted-acryloyl)-N-(3,4,5-trimethoxybenzoyl)piperazinederivative, in a yield which varied from 50 to 99%. When the desiredcompound was obtained in a non-crystalline solid, the compound waspulverized and dried; when it was obtained in a crystalline form, thecompound was recrystallized from a suitable solvent (specified in theExample), to afford a sample for biological tests.

EXAMPLE 7

1-[(E)-3-(3,4-Dimethoxyphenyl)cinnamoyl]-4(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(3,4-dimethoxyphenyl)cinnamic acid (prepared asdescribed in Preparation 6) as a powder in a yield of 78%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.70-3.70(8H, multiplet); 3.81 (3H, singlet); 3.84 (9H, singlet); 3.90 (3H,singlet); 6.25 (1H, singlet); 6.52 (2H, singlet); 6.76-6.88 (3H,multiplet); 7.27-7.42 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1585, 1515,1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 546 (M⁺), 351, 279, 267, 195.

EXAMPLE 8

1-[(Z)-3-(3,4-Dimethoxyphenyl)cinnamoyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3,4-dimethoxyphenyl)cinnamic acid (prepared asdescribed in Preparation 7) as a powder in a yield of 88%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.85 (3H, singlet); 3.86 (9H, singlet); 3.92 (3H,singlet); 6.22 (1H, singlet); 6.55 (2H, singlet); 6.80 (1H, doublet ofdoublets, J=8.30 & 1.46 Hz); 6.86 (1H, doublet, J=8.30 Hz); 6.86-6.88(1H, multiplet); 7.28-7.40 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1585, 1515,1460, 1420, 1335, 1130.

Mass Spectrum (m/z): 546 (M⁺), 351, 279, 267, 195.

EXAMPLE 9

4-(3,4,5-Trimethoxybenzoyl)-1-[(E)-3-(3,4,5-trimethoxyphenyl)cinnamoyl]piperazine

Prepared from (E)-3-(3,4,5-trimethoxyphenyl)cinnamic acid (prepared asdescribed in Preparation 10) as crystals, melting at 166°-168° C. (afterrecrystallisation from a mixture of methylene chloride, diethyl etherand hexane), in a yield of 74%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.70-3.70(8H, multiplet); 3.78 (3H, singlet); 3.846 (9H, singlet); 3.850 (3H,singlet); 3.87 (3H, singlet); 6.26 (1H, singlet); 6.47 (2H, singlet);6.53 (2H, singlet); 7.28-7.42 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1585, 1505,1460, 1415, 1330, 1125.

Mass Spectrum (m/z): 576 (M⁺), 381, 297, 279, 195.

EXAMPLE 10

4-(3,4,5-Trimethoxybenzoyl)-1-[(Z)-3-(3,4,5-trimethoxyphenyl)cinnamoyl]piperazine

Prepared from (Z)-3-(3,4,5-trimethoxyphenyl)cinnamic acid (prepared asdescribed in Preparation 11) as crystals, melting at 149°-151° C. (afterrecrystallisation from a mixture of methylene chloride, diethyl etherand hexane), in a yield of 79%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.77 (6H, singlet); 3.85 (3H, singlet); 3.86 (6H,singlet); 3.89 (3H, singlet); 6.25 (1H, singlet); 6.53 (2H, singlet);6.54 (2H, singlet); 7.28-7.40 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1585, 1505,1460, 1415, 1335, 1125.

EXAMPLE 11

1-[(E)-3-(3-Methoxy-4-propoxyphenyl)cinnamoyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(3-methoxy-4-propoxyphenyl)cinnamic acid (preparedas described in Preparation 14) as a powder in a yield of 91%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.04 (3H,triplet, J=7.32 Hz); 1.88 (2H, multiplet); 2.70-3.65 (8H, multiplet);3.79 (3H, singlet); 3.84 (6H, singlet); 3.85 (3H, singlet); 3.99 (2H,triplet, J=6.83 Hz); 6.24 (1H, singlet); 6.53 (2H, singlet); 6.75-6.85(3H, multiplet); 7.27-7.43 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1600, 1590,1510, 1460, 1425, 1330, 1130.

Mass Spectrum (m/z): 574 (M⁺), 531, 379, 295, 279, 195.

EXAMPLE 12

1-[(Z)-3-(3-Methoxy-4-propoxyphenyl)cinnamoyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3-methoxy-4-propoxyphenyl)cinnamic acid (preparedas described in Preparation 15) as a powder in a yield of 91%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.06 (3H,triplet, J=7.32 Hz); 1.89 (2H, multiplet); 2.80-3.70 (8H, multiplet);3.78 (3H, singlet); 3.85 (3H, singlet); 3.86 (6H, singlet); 4.00 (3H,triplet, J=6.84 Hz); 6.20 (1H, singlet); 6.55 (2H, singlet); 6.78 (1H,doublet of doublets, J=8.30 & 1.46 Hz); 6.85-6.95 (2H, multiplet);7.27-7.40 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1600, 1590,1515, 1465, 1420, 1335, 1130.

Mass Spectrum (m/z): 574 (M⁺), 531, 379, 295, 279, 195.

EXAMPLE 13

1-[(E)-3-(3,4-Dipropoxyphenyl)cinnamoyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(3,4-dipropoxyphenyl)cinnamic acid (prepared asdescribed in Preparation 18) as a powder in a yield of 87%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.01 (3H,triplet, J=7.33 Hz); 1.05 (3H, triplet, J=7.33 Hz); 1.85 (4H,multiplet); 2.70-3.70 (8H, multiplet); 3.84 (9H, singlet); 3.84 (6H,singlet); 3.85 (3H, singlet); 3.88 (2H, triplet, J=6.83 Hz); 3.97 (2H,triplet, J=6.84 Hz); 6.23 (1H, singlet); 6.53 (2H, singlet); 6.80 (3H,singlet); 7.25-7.40 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1600, 1590,1510, 1460, 1425, 1330, 1130.

Mass Spectrum (m/z): 602 (M⁺), 559, 517, 407, 323, 195.

EXAMPLE 14

1-[(Z)-3-(3,4-Dipropoxyphenyl)cinnamoyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3,4-dipropoxyphenyl)cinnamic acid (prepared asdescribed in Preparation 19) as a powder in a yield of 88%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.01 (3H,triplet, J=7.32 Hz); 1.06 (3H, triplet, J=7.32 Hz); 1.70-1.95 (4H,multiplet); 2.70-3.70 (8H, multiplet); 3.85 (9H, singlet); 3.85-3.92(2H, multiplet); 3.99 (2H, triplet, J=6.84 Hz); 6.19 (1H, multiplet);6.55 (2H, singlet); 6.75-6.90 (3H, multiplet); 7.28-7.40 (5H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1600, 1590,1510, 1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 602 (M⁺), 559, 517, 407, 323, 195.

EXAMPLE 15

1-[(E)-3-(4-Chlorophenyl)-3-(3,4-dimethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylic acid(prepared as described in Preparation 22) as a powder in a yield of 89%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.82 (3H, singlet); 3.86 (9H, singlet); 3.90 (3H,singlet); 6.28 (1H, singlet); 6.56 (2H, singlet); 6.75 (1H, broadsinglet); 6.81 (2H, broad singlet); 7.20-7.38 (4H, AB-like multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1585, 1510,1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 580 (M⁺, ³⁵ Cl), 385, 301, 279, 195.

EXAMPLE 16

1-[(Z)-3-(4-Chlorophenyl)-3-(3,4-dimethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylic acid(prepared as described in Preparation 23) as a powder in a yield of 71%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.80 (3H, singlet); 3.86 (9H, singlet); 3.92 (3H,singlet); 6.20 (1H, singlet); 6.55 (2H, singlet); 6.78 (1H, doublet ofdoublets, J=8.25 & 1.95 Hz); 6.86 (1H, doublet, J=8.25 Hz); 6.81-6.87(1H, multiplet); 7.20-7.36 (4H, AB-like multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1635, 1595, 1515,1465, 1425, 1335, 1135.

Mass Spectrum (m/z): 580 (M⁺, ³⁵ Cl), 385, 301, 279, 195.

EXAMPLE 17

1-[(Z)-3-(3-Chlorophenyl)-3-(3,4-dimethoxyphenyl)acryloyl]-4-(3,4,5,-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3-Chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylic acid(prepared as described in Preparation 26) as a powder in a yield of 88%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.82 (3H, singlet); 3.86 (9H, singlet); 3.90 (3H,singlet); 6.29 (1H, singlet); 6.57 (2H, singlet); 6.77 (1H, broadsinglet); 6.82 (2H, multiplet); 7.15-7.43 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1600, 1590,1515, 1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 580 (M⁺, ³⁵ Cl), 385, 301, 279, 195.

EXAMPLE 18

1-[(E)-3-(3-Chlorophenyl)-3-(3,4-dimethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3-chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylic acid(prepared as described in Preparation 27) as a powder in a yield of 90%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.81 (3H, singlet); 3.86 (9H, singlet); 3.92 (3H,singlet); 6.22 (1H, singlet); 6.55 (2H, singlet); 6.78 (1H, doublet ofdoublets, J=8.30 & 1.95 Hz); 6.85 (1H, multiplet); 6.87 (1H, doublet,J=8.30 Hz); 7.13-7.38 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1590, 1515,1460, 1420, 1330, 1260, 1130.

Mass Spectrum (m/z): 580 (M⁺, ³⁵ Cl), 385, 301, 279, 195.

EXAMPLE 19

1-[(E)-3-(4-Chlorophenyl)-3-(2,3-dimethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(4-chlorophenyl)-3-(2,3-dimethoxyphenyl)acrylic acid(prepared as described in Preparation 30) as a powder in a yield of 85%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.57 (3H, singlet); 3.86 (9H, singlet); 3.87 (3H,singlet); 6.17 (1H, singlet); 6.55 (2H, singlet); 6.75 (1H, doublet ofdoublets, J=7.81 & 1.46 Hz); 6.93 (1H, doublet of doublets, J=8.30 &1.46 Hz); 7.04 (1H, triplet, J=8.30 Hz); 7.25 (2H, doublet ofmultiplets, J=8.79 Hz); 7.29 (2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1635, 1595, 1470,1430, 1335, 1135.

Mass Spectrum (m/z): 580 (M⁺, ³⁵ Cl), 549, 301, 195.

EXAMPLE 20

1-[(Z)-3-(4-Chlorophenyl)-3-(2,3-dimethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(4-chlorophenyl)-3-(2,3-dimethoxyphenyl)acrylic acid(prepared as described in Preparation 31) as a powder in a yield of 94%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.90-3.70(8H, multiplet); 3.855 (9H, singlet); 3.86 (6H, singlet); 6.38 (1H,singlet); 6.57 (2H, singlet); 6.86 (1H, doublet of doublets, J=8.30 &1.47 Hz); 6.96 (1H, doublet of doublets, J=8.30 & 1.47 Hz); 7.07 (1H,triplet, J=8.30 Hz); 7.20 (2H, doublet of multiplets, J=8.79 Hz); 7.29(2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1585, 1460,1420, 1330, 1125.

Mass Spectrum (m/z): 580 (M⁺, ³⁵ Cl), 549, 301, 195.

EXAMPLE 21

1-[(Z)-3-(4-Chlorophenyl)-3-(4-isobutoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(4-chlorophenyl)-3-(4-isobutoxyphenyl)acrylic acid(prepared as described in Preparation 34) as crystals melting at122°-124° C. (after recrystallisation from a mixture of diethyl etherand hexane), in a yield of 75%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.03 (6H,doublet, J=6.83 Hz); 2.09 (1H, multiplet); 2.80-3.65 (8H, multiplet);3.73 (2H, doublet, J=6.34 Hz); 3.86 (9H, singlet); 6.26 (1H, singlet);6.56 (2H, singlet); 6.84 (2H, doublet of multiplets, J=8.30 Hz); 7.17(2H, doublet of multiplets, J=8.30 Hz); 7.22 (2H, doublet of multiplets,J=8.30 Hz); 7.34 (2H, doublet of multiplets, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1605, 1590,1510, 1460, 1425, 1330, 1175, 1130.

Mass Spectrum (m/z): 592 (M⁺, ³⁵ Cl), 535, 397, 313, 279, 257, 195.

EXAMPLE 22

1-[(E)-3-(4-Chlorophenyl)-3-(4-isobutoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(4-chlorophenyl)-3-(4-isobutoxy-phenyl)acrylic acid(prepared as described in Preparation 35) as crystals melting at128°-129° C. (after recrystallisation from a mixture of diethyl etherand hexane), in a yield of 59%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.04 (6H,doublet, J=6.84 Hz); 2.10 (1H, multiplet); 2.70-3.65 (8H, multiplet);3.75 (1H, doublet, J=6.35 Hz); 3.84 (6H, singlet); 3.85 (3H, singlet);6.18 (1H, singlet); 6.54 (2H, singlet); 6.88 (2H, doublet of multiplets,J=8.79 Hz); 7.17 (2H, doublet of multiplets, J=8.79 Hz); 7.21 (2H,doublet of multiplets, J=8.30 Hz); 7.30 (2H, doublet of multiplets,J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1605, 1590,1510, 1490, 1460, 1425, 1330, 1285, 1175, 1130.

Mass Spectrum (m/z): 592 (M⁺, ³⁵ Cl), 535, 397, 313, 279, 257, 195.

EXAMPLE 23

1-[(Z)-3-(4-Chlorophenyl)-3-(4-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(4-chlorophenyl)-3-(4-propoxy-phenyl)acrylic acid(prepared as described in Preparation 38) as a powder in a yield of 76%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.04 (3H,triplet, J=7.32 Hz); 1.75-1.90 (2H, multiplet); 2.80-3.65 (8H,multiplet); 3.86 (9H, singlet); 3.93 (2H, triplet, J=6.84 Hz); 6.26 (1H,singlet); 6.56 (2H, singlet); 6.85 (2H, doublet of multiplets, J=8.79Hz); 7.17 (2H, doublet of multiplets, J=8.79 Hz); 7.22 (2H, doublet ofmultiplets, J=8.79 Hz); 7.34 (2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1605, 1590,1510, 1460, 1425, 1330, 1130.

Mass Spectrum (m/z): 578 (M⁺, ³⁵ Cl), 535, 383, 299, 279, 195.

EXAMPLE 24

1-[(E)-3-(4-Chlorophenyl)-3-(4-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(4-chlorophenyl)-3-(4-propoxy-phenyl)acrylic acid(prepared as described in Preparation 39) as a powder in a yield of 74%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.06 (3H,triplet, J=7.33 Hz); 1.75-1.92 (2H, multiplet); 2.80-3.70 (8H,multiplet); 3.846 (6H, singlet); 3.850 (3H, singlet); 6.18 (1H,singlet); 6.54 (2H, singlet); 6.88 (2H, doublet of multiplets, J=8.78Hz); 7.17 (2H, doublet of multiplets, J=8.78 Hz); 7.24 (2H, doublet ofmultiplets, J=8.30 Hz); 7.30 (2H, doublet of multiplets, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1605, 1590,1510, 1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 578 (M⁺, ³⁵ Cl), 535, 383, 299, 279, 195.

EXAMPLE 25

1-[Bis(4-fluorophenyl)acryloyl]-4-(3,4,5-trimethoxy-benzoyl)piperazine

Prepared from 3,3-bis(4-fluorophenyl)acrylic acid as a powder in a yieldof 76%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.70-3.70(8H, multiplet); 3.85 (9H, singlet); 6.27 (1H, singlet); 6.56 (2H,singlet); 6.97-7.13 (4H, multiplet); 7.20-7.33 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1600, 1585,1505, 1460, 1420, 1330, 1125.

Mass Spectrum (m/z): 522 (M⁺), 327, 279, 243, 195.

EXAMPLE 26

1-[(E)-3-(4-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(4-fluorophenyl)-3-(3,4,5-trimethoxyphenyl)acrylicacid (prepared as described in Preparation 42) as crystals, melting at195°-197° C. (after recrystallisation from a mixture of methylenechloride, diethyl ether and hexane), in a yield of 77%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.79 (6H, singlet); 3.86 (9H, singlet); 3.87 (3H,singlet); 6.27 (1H, singlet); 6.45 (2H, singlet); 6.56 (2H, singlet);7.05-7.13 (2H, multiplet); 7.25-7.33 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1585, 1505,1460, 1415, 1330, 1125.

Mass Spectrum (m/z): 594 (M⁺), 315, 279, 195.

EXAMPLE 27

1-[(Z)-3-(4-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(4-fluorophenyl)-3-(3,4,5-trimethoxyphenyl)acrylicacid (prepared as described in Preparation 43) as crystals, melting at130°-132° C. (after recrystallisation from a mixture of methylenechloride and diethyl ether), in a yield of 78%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.77 (6H, singlet); 3.85 (3H, singlet); 3.86 (6H,singlet); 3.89 (3H, singlet); 6.20 (1H, singlet); 6.51 (2H, singlet);6.54 (2H, singlet); 7.00-7.09 (2H, multiplet); 7.26-7.35 (2H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1600, 1585,1505, 1460, 1415, 1125.

Mass Spectrum (m/z): 594 (M⁺), 315, 279, 195.

EXAMPLE 28

1-[Bis(3,4-dimethoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from 3,3-bis(3,4-dimethoxyphenyl)acrylic acid as a powder in ayield of 74%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.81 (3H, singlet); 3.82 (3H, singlet); 3.86 (9H,singlet); 3.91 (3H, singlet); 3.92 (3H, singlet); 6.16 (1H, singlet);6.56 (2H, singlet); 6.80-6.95 (6H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1600, 1585,1515, 1460, 1420, 1330, 1250, 1125.

Mass Spectrum (m/z): 606 (M⁺), 411, 327, 195.

EXAMPLE 29

1-[(E)-3-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)acrylicacid (prepared as described in Preparation 46) as a powder in a yield of54%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.81 (3H, singlet); 3.85 (12H, singlet); 3.90 (3H,singlet); 6.16 (1H, singlet); 6.55 (2H, singlet); 6.76-6.85 (3H,multiplet); 6.89 (2H, doublet or multiplets, J=8.78 Hz); 7.22 (2H,doublet of multiplets, J=8.78 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1600, 1585,1510, 1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 576 (M⁺), 381, 297, 195.

EXAMPLE 30

1-[(Z)-3-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)acrylicacid (prepared as described in Preparation 47) as a powder in a yield of73%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.90-3.70(8H, multiplet); 3.80 (3H, singlet); 3.83 (3H, singlet); 3.86 (9H,singlet); 3.92 (3H, singlet); 6.15 (1H, singlet); 6.55 (2H, singlet);6.78-6.91 (5H, multiplet); 7.12-7.26 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1605, 1585,1510, 1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 576 (M⁺), 381, 297, 279, 195.

EXAMPLE 31

1-[(Z)-3-(3,4-Dichlorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid(prepared as described in Preparation 50) as a powder in a yield of 85%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.10-3.70(8H, multiplet); 3.83 (3H, singlet); 3.857 (3H, singlet); 3.861 (6H,singlet); 6.32 (1H, singlet); 6.58 (2H, singlet); 6.87 (2H, doublet ofmultiplets, J=8.79 Hz); 7.13 (1H, doublet of doublets, J=8.30 & 1.95Hz); 7.18 (2H, doublet of multiplets, J=8.79 Hz); 7.36 (1H, doublet,J=1.95 Hz); 7.45 (1H, doublet, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1605, 1585,1510, 1460, 1420, 1330, 1125.

Mass Spectrum (m/z): 584 (M⁺, ³⁵ Cl), 389, 305, 279, 195.

EXAMPLE 32

1-[(E)-3-(3,4-Dichlorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid(prepared as described in Preparation 51) as a powder in a yield of 84%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.85 (12H, singlet); 6.21 (1H, singlet); 6.54 (2H,singlet); 6.90 (2H, doublet of multiplets, J=8.79 Hz); 7.10 (1H, doubletof doublets, J=8.30 & 1.95 Hz); 7.18 (2H, doublet of multiplets, J=8.79Hz); 7.38 (1H, doublet, J=1.95 Hz); 7.40 (1H, doublet, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1605, 1585,1510, 1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 584 (M⁺, ³⁵ Cl), 389, 305, 279, 195.

EXAMPLE 33

1-[(E)-3-(3,4-Dimethoxyphenyl)-3-(3-trifluoromethylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from(E)-3-(3,4-dimethoxyphenyl)-3-(3-trifluoromethylphenyl)acrylic acid(prepared as described in Preparation 54) as a powder in a yield of 74%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.90-3.70(8H, multiplet); 3.82 (3H, singlet); 3.848 (6H, singlet); 3.853 (3H,singlet); 3.91 (3H, singlet); 6.37 (1H, singlet); 6.56 (2H, singlet);6.77 (1H, broad singlet); 6.79-6.88 (2H, multiplet); 7.47-7.60 (3H,multiplet); 7.60-7.71 (1H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1600, 1585,1510, 1460, 1420, 1325, 1300, 1170, 1125.

Mass Spectrum (m/z): 614 (M⁺), 419, 335, 307, 279, 195.

EXAMPLE 34

1-[(Z)-3-(3,4-Dimethoxyphenyl)-3-(3-trifluoromethylphenyl)acryloyl[-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from(Z)-3-(3,4-dimethoxyphenyl)-3-(3-trifluoromethylphenyl)acrylic acid(prepared as described in Preparation 55) as a powder in a yield of 50%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.81 (3H, singlet); 3.85 (3H, singlet); 3.86 (6H,singlet); 3.93 (3H, singlet); 6.26 (1H, singlet); 6.56 (2H, singlet);6.78 (1H, doublet of doublets, J=8.30 & 1.96 Hz); 6.86 (1H, multiplet);6.87 (1H, doublet, J=8.30 Hz); 7.43-7.53 (2H, multiplet); 7.53-7.67 (2H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1600, 1585,1515, 1460, 1420, 1325, 1255, 1165, 1125.

Mass Spectrum (m/z): 614 (M⁺), 419, 335, 307, 279, 195.

EXAMPLE 35

1-[(E)-3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(3,4-dimethoxyphenyl)-3-(4-methylphenyl)acrylic acid(prepared as described in Preparation 58) as a powder in a yield of 89%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.39 (3H,singlet); 2.80-3.70 (8H, multiplet); 3.81 (3H, singlet); 3.848 (6H,singlet); 3.851 (3H, singlet); 3.89 (3H, singlet); 6.20 (1H, singlet);6.54 (2H, singlet); 6.79 (1H, broad singlet); 6.80-6.90 (2H, multiplet);7.17 (4H, singlet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1620, 1600, 1585,1510, 1460, 1420, 1330, 1125.

Mass Spectrum (m/z): 560 (M⁺), 365, 281, 279, 195.

EXAMPLE 36

1-[(Z)-3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3,4-dimethoxyphenyl)-3-(4-methylphenyl)acrylic acid(prepared as described in Preparation 59) as a powder in a yield of 99%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.37 (3H,singlet); 2.80-3.70 (8H, multiplet); 3.80 (3H, singlet); 3.85 (3H,singlet); 3.86 (6H, singlet); 3.91 (3H, singlet); 6.19 (1H, singlet);6.55 (2H, singlet); 6.80 (1H, doublet of doublets, J=8.30 & 1.46 Hz);6.84 (1H, multiplet); 6.85 (1H, doublet, J=8.30 Hz); 7.14 (2H, doublet,J=8.30 Hz); 7.19 (2H, doublet, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1585, 1510,1460, 1420, 1330, 1255, 1125.

Mass Spectrum (m/z): 560 (M⁺), 365, 281, 279, 195.

EXAMPLE 37

1-[(Z)-3-(3,4-Dichlorophenyl)-3-(3-methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3,4-dichlorophenyl)-3-(3-methylphenyl)acrylic acid(prepared as described in Preparation 62) as a powder, in a yield of91%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.34 (3H,singlet); 2.90-3.70 (8H, multiplet); 3.857 (3H, singlet); 3.862 (6H,singlet); 6.36 (1H, singlet); 6.58 (2H, singlet); 7.00-7.07 (2H,multiplet); 7.13 (1H, doublet of doublets, J=8.30 Hz); 7.16-7.28 (2H,multiplet); 7.36 (1H, doublet, J=1.96 Hz); 7.45 (1H, doublet, J=8.30Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1635, 1590, 1465,1425, 1335, 1130.

Mass Spectrum (m/z): 568 (M⁺, ³⁵ Cl), 373, 289, 279, 195.

EXAMPLE 38

1-[(E)-3-(3,4-Dichlorophenyl)-3-(3-methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(3,4-dichlorophenyl)-3-(3-methylphenyl)acrylic acid(prepared as described in Preparation 63) as a powder, in a yield of92%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.35 (3H,singlet); 2.70-3.70 (8H, multiplet); 3.84 (6H, singlet); 3.85 (3H,singlet); 6.27 (1H, singlet); 6.53 (2H, singlet); 7.02-7.14 (3H,multiplet); 7.18-7.32 (2H, multiplet); 7.36-7.44 (3H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1610, 1590,1465, 1425, 1335, 1130.

Mass Spectrum (m/z): 568 (M⁺, ³⁵ Cl), 373, 289, 279, 195.

EXAMPLE 39

1-[(E)-3-(3,4-Dimethoxyphenyl)-3-(3-methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(3,4-dimethoxyphenyl)-3-(3-methylphenyl)acrylic acid(prepared as described in Preparation 66) as a powder, in a yield of83%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.34 (3H,singlet); 2.70-3.70 (8H, multiplet); 3.81 (3H, singlet); 3.846 (6H,singlet); 3.850 (3H, singlet); 3.90 (3H, singlet); 6.21 (1H, singlet);6.54 (2H, singlet); 6.76-6.88 (3H, multiplet); 7.06-7.13 (2H,multiplet); 7.16-7.30 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1605, 1590,1515, 1465, 1425, 1330, 1130.

Mass Spectrum (m/z): 560 (M⁺), 365, 281, 279, 195.

EXAMPLE 40

1-[(Z)-3-(3,4-Dimethoxyphenyl)-3-(3-methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3,4-dimethoxyphenyl)-3-(3-methylphenyl)acrylic acid(prepared as described in Preparation 67) as a powder, in a yield of83%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.34 (3H,singlet); 2.80-3.70 (8H, multiplet); 3.80 (3H, singlet); 3.85 (3H,singlet); 3.86 (6H, singlet); 3.92 (3H, singlet); 6.20 (1H, singlet);6.55 (2H, singlet); 6.77-6.90 (3H, multiplet); 7.06-7.28 (4H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1600, 1590,1515, 1465, 1425, 1330, 1260, 1130.

Mass Spectrum (m/z): 560 (M⁺), 365, 281, 279, 195.

EXAMPLE 41

1-[3,3-Bis(3-chlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from 3,3-bis(3-chlorophenyl)acrylic acid (prepared as describedin Preparation 110) as a powder, in a yield of 86%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.86 (9H, singlet); 6.36 (1H, singlet); 6.56 (2H,singlet); 7.10-7.20 (2H, multiplet); 7.27-7.43 (6H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1590, 1460,1420, 1330, 1130.

Mass Spectrum (m/z): 554 (M⁺, ³⁵ l), 359, 279, 275, 195.

EXAMPLE 42

1-[(Z)-3-(2-Chlorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(2-chlorophenyl)-3-(4-methoxyphenyl)acrylic acid(prepared as described in Preparation 69) as a powder, in a yield of91%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.80(8H, multiplet); 3.81 (3H, singlet); 3.86 (9H, singlet); 6.54 (1H,singlet); 6.58 (2H, singlet); 6.85 (2H, doublet of multiplets, J=8.79Hz); 7.18 (2H, doublet of multiplets, J=8.79 Hz); 7.29-7.45 (4H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1605, 1585,1510, 1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 550 (M⁺, ³⁵ l), 515, 279, 271, 195.

EXAMPLE 43

1-[(Z)-3-(3-Chlorophenyl)-3-(3-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3-chlorophenyl)-3-(3-methoxyphenyl)acrylic acid(prepared as described in Preparation 72) as a powder, in a yield of81%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.78 (3H, singlet); 3.85 (9H, singlet); 6.35 (1H,singlet); 6.56 (2H, singlet); 6.56-6.94 (3H, multiplet); 7.16-7.40 (5H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1600, 1585,1460, 1420, 1330, 1125.

Mass Spectrum (m/z): 550 (M⁺, ³⁵ Cl), 355, 279, 271, 195.

EXAMPLE 44

1-[(E)-3-(3-Chlorophenyl)-3-(3-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(3-chlorophenyl)-3-(3-methoxyphenyl)acrylic acid(prepared as described in Preparation 73) as a powder, in a yield of82%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.77 (3H, singlet); 3.85 (9H, singlet); 6.29 (1H,singlet); 6.54 (2H, singlet); 6.80-6.87 (2H, multiplet); 6.90-6.97 (1H,multiplet); 7.12-7.19 (1H, multiplet); 7.22-7.37 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1600, 1585,1460, 1420, 1330, 1125.

Mass Spectrum (m/z): 550 (M⁺, ³⁵ Cl), 355, 279, 271, 195.

EXAMPLE 45

1-[(Z)-3-(3-Chlorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3-chlorophenyl)-3-(4-methoxyphenyl)acrylic acid(prepared as described in Preparation 76) as a powder, in a yield of81%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.83 (3H, singlet); 3.85 (9H, singlet); 6.28 (1H,singlet); 6.56 (2H, singlet); 6.86 (2H, doublet of multiplets, J=8.79Hz); 7.19 (2H, doublet of multiplets, J=8.79 Hz); 7.26-7.40 (4H,multiplet);

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1605, 1585,1510, 1460, 1420, 1330, 1125.

Mass Spectrum (m/z): 550 (M⁺, ³⁵ Cl), 355, 279, 271, 195.

EXAMPLE 46

1-[(E)-3-(3-Chlorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(3-chlorophenyl)-3-(4-methoxyphenyl)acrylic acid(prepared as described in Preparation 77) as a powder, in a yield of82%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.80-3.70(8H, multiplet); 3.85 (12H, singlet); 6.21 (2H, singlet); 6.55 (2H,singlet); 6.90 (2H, doublet of multiplets, J=8.79 Hz); 7.20 (2H, doubletof multiplets, J=8.79 Hz); 7.12-7.36 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1600, 1585,1510, 1460, 1420, 1330, 1125.

Mass Spectrum (m/z): 550 (M⁺, ³⁵ Cl), 355, 279, 271, 195.

EXAMPLE 47

1-[(Z)-3-(2-Naphthyl)-3-phenylacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(2-naphthyl)-3-phenylacrylic acid (prepared asdescribed in Preparation 113) as a powder, in a yield of 94%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.50-3.70(8H, multiplet); 3.77 (3H, singlet); 3.82 (6H, singlet); 6.39 (3H,singlet); 7.28-7.40 (6H, multiplet); 7.46-7.57 (2H, multiplet);7.78-7.90 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1600, 1585,1460, 1425, 1330, 1130.

Mass Spectrum (m/z): 536 (M⁺), 341, 279, 257, 195.

EXAMPLE 48

1-[(E)-3-(2-Naphthyl)-3-phenylacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(2-naphthyl)-3-phenylacrylic acid (prepared asdescribed in Preparation 114) as a powder, in a yield of 88%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.60-3.70(8H, multiplet); 3.85 (9H, singlet); 6.44 (1H, singlet); 6.54 (2H,singlet); 7.30-7.54 (8H, multiplet); 7.71 (1H, broad singlet); 7.74-7.88(3H, singlet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1605, 1595,1460, 1420, 1330, 1125.

Mass Spectrum (m/z): 536 (M⁺), 341, 279, 257, 195.

EXAMPLE 49

1-[(Z)-3-(3,4-Dichlorophenyl)-3-(4-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3,4-dichlorophenyl)-3-(4-propoxyphenyl)acrylic acid(prepared as described in Preparation 80), as a powder, in a yield of84%

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.04 (3H,triplet, J=7.32 Hz); 1.73-1.90 (2H, multiplet); 3.10-3.70 (8H,multiplet); 3.86 (9H, multiplet); 3.93 (2H, triplet, J=6.35 Hz); 6.31(1H, singlet); 6.58 (2H, singlet); 6.86 (2H, doublet of multiplets,J=8.79 Hz); 7.13 (1H, doublet of doublets, J=8.30 & 1.46 Hz); 7.17 (2H,doublet of multiplets, J=8.79 Hz); 7.36 (1H, doublet, J=1.46 Hz); 7.45(1H, doublet, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1605, 1590,1510, 1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 612 (M⁺, ³⁵ Cl), 569, 417, 333, 279, 195.

EXAMPLE 50

1-[(E)-3-(4-Ethoxy-3-methoxyphenyl)-3-phenylacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(4-ethoxy-3-methoxyphenyl)cinnamic acid (prepared asdescribed in Preparation 84), as a powder, in a yield of 93%

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.47 (3H,triplet, J=6.84 Hz); 2.50-3.70 (8H, multiplet); 3.80 (3H, singlet); 3.84(9H, singlet); 4.11 (2H, quartet, J=6.84 Hz); 6.25 (1H, singlet); 6.53(2H, singlet); 6.79 (1H, broad singlet); 6.80 (2H, broad singlet);7.27-7.34 (2H, multiplet); 7.34-7.41 (3H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1600, 1590,1510, 1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 560 (M⁺), 545, 365, 281, 195.

EXAMPLE 51

1-[(E)-3-(4-Butoxy-3-methoxyphenyl)-3-phenylacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(4-butoxy-3-methoxyphenyl)cinnamic acid (prepared asdescribed in Preparation 88), as a powder, in a yield of 79%

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 0.98 (3H,triplet, J=7.32 Hz); 1.45-1.58 (2H, multiplet); 1.75-1.90 (2H,multiplet); 2.60-3.70 (8H, multiplet); 3.79 (3H, singlet); 3.84 (9H,singlet); 6.24 (1H, singlet); 6.53 (2H, singlet); 6.76-6.86 (3H,multiplet); 7.26-7.34 (2H, multiplet); 7.34-7.42 (3H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1600, 1590,1510, 1460, 1420, 1330, 1130.

Mass Spectrum (m/z): 588 (M⁺), 545, 531, 393, 309, 279, 195.

EXAMPLE 52

1-[(Z)-3-(3,4-Dichlorophenyl)-3-(4-ethylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (Z)-3-(3,4-dichlorophenyl)-3-(4-ethylphenyl)acrylic acid(prepared as described in Preparation 91), as a powder, in a yield of81%

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.25 (3H,triplet, J=7.32 Hz); 2.67 (2H, quartet, J=7.32 Hz); 3.00-3.70 (8H,multiplet); 3.86 (9H, multiplet); 6.36 (1H, singlet); 6.58 (2H,singlet); 7.13 (1H, doublet of doublets, J=8.30 & 1.96 Hz); 7.12-7.22(4H, multiplet); 7.36 (1H, doublet, J=1.96 Hz); 7.45 (1H, doublet,J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1590, 1460,1420, 1330, 1130.

Mass Spectrum (m/z): 582 (M⁺, ³⁵ Cl), 387, 303, 279, 195.

EXAMPLE 53

1-[(E)-3-Phenyl-3-(4-propoxyphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(4-propoxyphenyl)cinnamic acid (prepared asdescribed in Preparation 95), as a powder, in a yield of 78%

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 1.03 (3H,triplet, J=7 Hz); 1.50-2.15 (2H, multiplet); 2.80-3.70 (8H, multiplet);3.83 (9H, singlet); 3.84 (2H, triplet, J=7 Hz); 6.26 (1H, singlet); 6.56(2H, singlet); 6.86 (2H, doublet of multiplets, J=9 Hz); 7.24 (2H,doublet of multiplets, J=9 Hz); 7.25-7.60 (5H, multiplet).

EXAMPLE 54

1-[(E)-3-(3,4-Methylenedioxyphenyl)-3-phenylacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from (E)-3-(3,4-methylenedioxyphenyl)cinnamic acid (prepared asdescribed in Preparation 96), as a powder, in a yield of 94%

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 2.60-3.70(8H, multiplet); 3.84 (9H, singlet); 5.98 (2H, singlet); 6.23 (1H,singlet); 6.55 (2H, singlet); 6.78 (3H, singlet); 7.20-7.60 (5H,multiplet).

EXAMPLE 55

1-[(E)-3-(3-Methoxy-4-propoxyphenyl)-3-(3-methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from(E)-3-(3-methoxy-4-propoxyphenyl)-3-(3-methylphenyl)acrylic acid(prepared as described in Preparation 100), as a powder, in a yield of69%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.04 (3H,triplet, J=7.33 Hz); 1.80-1.95 (2H, multiplet); 2.34 (3H, singlet);2.70-3.70 (8H, multiplet); 3.80 (3H, singlet); 3.85 (9H, singlet); 3.99(2H, triplet, J=6.84 Hz); 6.21 (1H, singlet); 6.54 (2H, singlet); 6.80(3H, broad singlet); 7.05-7.13 (2H, multiplet); 7.16-7.30 (2H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1600, 1590,1510, 1460, 1425, 1330, 1260, 1130.

Mass Spectrum (m/z): 588 (M⁺), 545, 393, 309, 279, 195.

EXAMPLE 56

1-[3,3-Bis(3-Methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from 3,3-bis(3-methylphenyl)acrylic acid (prepared as describedin Preparation 103), as a powder, in a yield of 82%

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.34 (6H,singlet); 2.60-3.70 (8H, multiplet); 3.84 (9H, singlet); 6.24 (1H,singlet); 6.54 (2H, singlet); 7.02-7.12 (4H, multiplet); 7.13-7.29 (4H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1605, 1590,1460, 1425, 1330, 1130.

Mass Spectrum (m/z): 514 (M⁺, ³⁵ Cl), 319, 279, 235, 195.

EXAMPLE 57

1-[(E)-3,5-Diphenylpent-2-en-4-ynoyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Following a procedure similar to that described in Example 1, but using0.900 g of (E)-3,5-diphenylpent-2-en-4-ynoic acid (prepared as describedin Preparation 105), 1.574 g of the title compound was obtained as apowder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.40-4.00(8H, multiplet); 3.83 (3H, singlet); 3.85 (6H, singlet); 6.59 (2H,singlet); 6.74 (1H, singlet); 7.3-7.8 (10H, multiplet).

Mass spectrum (m/z): 510 (M⁺), 315, 279, 231, 195.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1615, 1590, 1490,1460, 1420, 1330, 1125.

Elemental analysis: Calculated for C₃₁ H₃₀ N₂ O₅ : C, 72.97%; H, 5.92%;N, 5.49%. Found: C, 72.65%; H, 6.10%; N, 5.45%.

EXAMPLE 58

1-[(2E,4Z)-3,5-Diphenylpent-2,4-dienoyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

0.025 g of 10% w/w palladium-on-barium sulfate and two drops ofquinoline were added to 5 ml of a methanol solution containing 0.250 gof1-[(E)-3,5-diphenylpent-2-en-4-ynoyl]-4-(3,4,5-trimethoxybenzoyl)piperazine(prepared as described in Example 58). Hydrogen gas was introduced intothe reaction mixture at room temperature and at atmospheric pressure.The reaction mixture was then shaken for 15 hours, after which thecatalyst was filtered off and the solvent was removed by distillationunder reduced pressure. The residue was subjected to moderate pressureliquid chromatography using a Lobar B column. 0.153 g of the titlecompound was obtained as a powder from those fractions eluted withmixtures of methylene chloride and ethyl acetate ranging from 3:2 to 1:3by volume.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.90-3.80(8H, multiplet): 3.86 (3H, singlet); 3.87 (6H, singlet); 6.38 (1H, broadsinglet); 6.58 (2H, singlet); 6.61 (1H, doublet of doublets, J=12.20 &1.95 Hz).

EXAMPLE 59

1-[3,3-Bis(4-methoxyphenyl)-2-methylacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Following a procedure similar to that described as the general syntheticmethod of Example 7, 0.673 g of the title compound was obtained aspowder from 0.511 g of 3,3-bis(4-methoxyphenyl)-2-methylacrylic acid(prepared as described in Preparation 108).

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.00 (3H,singlet); 2.95-3.45 (8H, multiplet); 3.80 (3H, singlet); 3.82 (3H,singlet); 3.846 (6H, singlet); 3.851 (3H, singlet); 6.53 (2H, singlet);6.75-7.20 (8H, multiplet).

Mass spectrum (m/z): 560 (M⁺); 545, 365, 281, 279, 195.

EXAMPLE 60

1-(3,3-Diphenylacryloyl)-4-(3,4,5-trimethoxybenzenesulfonyl)piperazine

0.371 g of phosphorus pentachloride was added to 8 ml of a methylenechloride solution containing 0.400 g of 3-phenylcinnamic acid in an icebath. The reaction solution was then stirred for 1 hour at 0° to 5° C.,after which it was condensed by evaporation under reduced pressure. 10ml of dry toluene were added to the residue, which was then evaporatedto dryness under reduced pressure. The residue was dissolved in 5 ml oftetrahydrofuran, and this solution was added to a mixture of 0.564 g ofN-(3,4,5-trimethoxybenzenesulfonyl) piperazine (prepared as described inPreparation 109), 0.300 g of sodium bicarbonate, 15 ml oftetrahydrofuran and 7.5 ml of water. The reaction solution was stirredfor 30 minutes at room temperature, and then poured into water, afterwhich it was extracted twice with methylene chloride. The combinedmethylene chloride extracts were washed with 10% w/v aqueoushydrochloric acid, with a saturated aqueous solution of sodiumbicarbonate and with a saturated aqueous solution of sodium chloride, inthat order. They were then dried over anhydrous sodium sulfate andcondensed by evaporation under reduced pressure. The residue wassubjected to column chromatography using 20 g of silica gel. 0.750 g ofthe title compound was obtained as crystals, melting at 163° C.-165° C.(after recrystallization from a mixture of ethyl acetate and hexane),from those fractions eluted with mixtures of methylene chloride andethyl acetate ranging from 3:2 to 1:3 by volume.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.17 (2H,triplet, J=4.76 Hz); 2.81 (2H, triplet, J=4.76 Hz); 3.35 (2H, triplet,J=4.76 Hz); 3.64 (2H, triplet, J=4.76 Hz); 3.92 (6H, singlet); 3.97 (3H,singlet); 6.21 (1H, singlet); 6.80 (2H, singlet); 7.00-7.40 (10H,multiplet).

Mass spectrum (m/z): 522 (M⁺), 458, 315, 291, 231, 207.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1595, 1500,1460, 1410, 1350, 1315, 1155, 1130.

Elemental analysis: Calculated for C₂₈ H₃₀ N₂ O₆ S: C, 64.35%; H, 5.79%;N, 5.36%; S, 6.14%. Found: C, 64.60%; H, 5.94%; N, 5.35%; S, 6.27%.

EXAMPLE 61

1-(3-Phenylcinnamoyl)-4-[3,4,5-trimethoxy(thiobenzoyl)]piperazine

0.836 g of phosphorus pentachloride was added to 18 ml of a methylenechloride solution containing 0.900 g of 3-phenylcinnamic acid, in an icebath. The mixture was then stirred for 1 hour at 0° to 5° C. At the endof this time, the reaction mixture was evaporated to dryness underreduced pressure, and then 20 ml of dry toluene was added to theresulting residue; the mixture was then evaporated to dryness; thisprocedure was then repeated. The resulting residue was dissolved in 5 mlof tetrahydrofuran, and this solution was added to a mixture of 1.189 gof 1-(3,4,5-trimethoxythiobenzoyl)piperazine, 0.674 g of sodiumbicarbonate, 25 ml of tetrahydrofuran and 12.5 ml of water, in an icebath. The reaction mixture was then stirred for 30 minutes at roomtemperature, after which it was poured into water and extracted twicewith methylene chloride. The methylene chloride extract was washed with10% w/v aqueous hydrochloric acid, with a saturated aqueous solution ofsodium bicarbonate and with water, in that order. It was then dried overanhydrous sodium sulfate and condensed by evaporation under reducedpressure. The residue was subjected to column chromatography through 40g of silica gel. Those fractions eluted with a 3:1 by volume mixture ofmethylene chloride and ethyl acetate were collected, and the eluentremoved, to give 1.860 g of the title compound as a powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.84 (1H,broad singlet); 3.23 (1H, broad singlet); 3.39 (1H, broad singlet); 3.51(2H, broad singlet); 3.69 (1H, broad singlet); 3.76 (1H, broad singlet);3.82, 3.84 (together 9H, both singlets); 4.17 (1H, broad singlet); 6.27,6.33 (1H, both singlets); 6.37, 6.44 (2H, both singlets); 7.20-7.50(10H, multiplet).

Mass spectrum (m/z): 502 (M⁺), 469, 335, 295, 211, 207, 178, 167.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1580, 1460,1425, 1340, 1280, 1125.

EXAMPLE 62

1-[3,3-Bis(4-methoxyphenyl)acryloyl]-4-[3,4,5-trimethoxy(thiobenzoyl)]piperazine

Following a procedure similar to that described in Example 61, but using0.400 g of 3,3-bis(4-methoxyphenyl)acrylic acid, 0.596 g of the titlecompound was obtained as a yellow powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.96, 3.23,3.45, 3.51, 4.20 (together 8H, 5 broad singlets); 3.82 (6H, singlet);3.85 (9H, singlet); 6.11, 6.16 (1H, both singlets); 6.38, 6.45 (2H, bothsinglets); 6.80-6.95 (4H, multiplet); 7.10-7.30 (4H, multiplet).

Mass spectrum (m/z): 562 (M⁺), 529, 335, 295, 267, 227, 211.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1625, 1605, 1585,1510, 1460, 1425, 1340, 1280, 1170, 1125.

Elemental analysis: Calculated for C₃₁ H₃₄ N₂ O₆ S: C, 66.17%; H, 6.09%;N, 4.98%; S, 5.70%. Found: C, 65.92%; H, 6.37%; N, 4.84%; S, 5.65%.

EXAMPLE 63

1-[3,3-Bis(4-fluorophenyl)]-4-[3,4,5-trimethoxy(thiobenzoyl)]piperazine

Following a procedure similar to that described in Example 61, but using0.300 g of 3,3-bis(4-fluorophenyl)acrylic acid, 0.574 g of the titlecompound was obtained as a yellow powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.04, 3.25,3.52, 3.78, 4.21 (together 8H, 5 broad singlets); 3.84 (9H, singlet);6.28 (1H, broad singlet); 6.45 (2H, singlet); 6.95-7.35 (8H, multiplet).

Mass spectrum (m/z): 538 (M⁺), 505, 335, 295, 243, 211.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1600, 1580,1505, 1460, 1425, 1340, 1125.

EXAMPLE 64

1-(3-Phenylcinnamoyl)-4-(3,4,5-trimethoxybenzyl)piperazine

Following a procedure similar to that described in Example 61, but using0.500 g of 3-phenylcinnamic acid and 0.653 g of1-(3,4,5-trimethoxybenzyl)piperazine, 0.897 g of the title compound wasobtained as a powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.88 (2H,triplet, J=5.13 Hz); 2.25 (2H, triplet, J=5.13 Hz); 3.28 (2H,multiplet); 3.28 (2H, singlet); 3.55 (2H, triplet, J=5.13 Hz); 3.83 (3H,singlet); 3.84 (6H, singlet); 6.30 (1H, singlet); 6.46 (2H, singlet);7.13-7.47 (10H, multiplet).

Mass Spectrum (m/z): 472 (M⁺), 457, 291, 265, 207, 181.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1595, 1460,1440, 1345, 1125.

EXAMPLE 65

1-[3,3-Diphenyl(thioacryloyl)]-4-[3,4,5-trimethoxy(thiobenzoyl)]piperazine

A solution of 1.000 g of1-(3-phenylcinnamoyl)-4-[3,4,5-trimethoxy(thiobenzoyl)]piperazine(prepared as described in Example 61) in 10 ml of benzene and 0.805 g ofLawesson's Reagent consisting mainly of[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide]was heated under reflux for 2 hours. At the end of this time, thereaction mixture was cooled to room temperature, poured into water andextracted twice with ethyl acetate. The extract was washed with water,dried over anhydrous sodium sulfate, and concentrated by distillationunder reduced pressure. The residue was purified by columnchromatography through 30 g of silica gel eluted with a 3:1 by volumemixture of hexane and ethyl acetate, to give 1.010 g of the titlecompound as a yellow powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.86-4.45(8H, multiplet); 3.82 & 3.84 (together 9H, each singlet); 6.36 & 6.37(together 2H, each singlet); 6.66 & 6.69 (together 1H, each singlet);7.15-7.50 (10H, multiplet).

Mass spectrum (m/z): 518 (M⁺), 485; 351; 307.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1580, 1475, 1425,1340, 1285, 1130.

EXAMPLE 66

1-[3,3-Bis(4-methoxyphenyl)thioacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

66(a) 1-[3,3-Bis(4-methoxyphenyl)acryloyl]piperazine

3.41 ml of diphenylphosphoryl azide and 1.09 ml of 1-formylpiperazinewere added to a 60 ml of a methylene chloride solution of 3.00 g of3,3-bis(4-methoxyphenyl)acrylic acid and 2.94 ml of triethylamine. Thereaction mixture was then stirred for 2 hours at room temperature, afterwhich it was poured into a saturated aqueous solution of sodiumbicarbonate and extracted twice with methylene chloride. The combinedextracts were washed with water, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was dissolved in 80 ml ofmethanol, and 40 ml of a 10% w/v aqueous solution of sodium hydroxidewere added to the resulting solution. The reaction mixture was stirredfor 18 hours at room temperature and then poured into water; it was thenextracted twice with methylene chloride. The combined extracts werewashed with water, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The residue was purified by columnchromatography through 80 g of silica gel eluted with mixtures ofmethylene chloride and methanol ranging from 19:1 to 4:1 by volume togive 3.00 g of 1-[3,3-bis(4-methoxyphenyl)acryloyl]piperazine as apowder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 2.08 (1H,singlet); 2.20-3.65 (8H, multiplet); 3.80 (6H, singlet); 6.13 (1H,singlet); 6.70-7.40 (8H, multiplet).

66(b) 1-[3,3-Bis(4-methoxyphenyl)thioacryloyl]piperazine

1.155 g of the 1-[3,3-bis(4-methoxyphenyl)acryloyl]piperazine [preparedas described in step (a) above] were dissolved in 12 ml of benzene, andthe resulting solution was heated under reflux for 2 hours with 1.326 gof Lawesson's Reagent. At the end of this time, the reaction mixture wascooled to room temperature, after which it was poured into water andextracted twice with ethyl acetate. The combined extracts were washedwith water, dried over anhydrous sodium sulfate, and concentrated byevaporation under reduced pressure. The residue was purified by columnchromatography through 30 g of silica gel eluted with a 19:1 by volumemixture of methylene chloride and methanol, to give 1.177 g of1-[3,3-bis(4-methoxyphenyl)thioacryloyl]piperazine as a powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 2.30 (2H,multiplet); 2.80 (2H, multiplet); 2.86 (1H, singlet); 3.48 (2H,multiplet); 3.80 (6H, singlet); 4.16 (2H, multiplet); 6.50 (1H,singlet); 6.70-7.50 (8H, multiplet).

66(c)1-[3,3-Bis(4-methoxyphenyl)thioacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

1.049 g of 1-[3,3-bis(4-methoxyphenyl)thioacryloyl]piperazine [preparedas described in step (b) above] and 0.29 ml of triethylamine weredissolved in 30 ml of methylene chloride, and 0.157 g of3,4,5-trimethoxybenzoyl chloride were added, whilst ice-cooling, to theresulting solution. The reaction mixture was then stirred for 1 hour atroom temperature, after which it was poured into water and extractedtwice with methylene chloride. The combined extracts were washed with10% w/v aqueous hydrochloric acid, with a saturated aqueous solution ofsodium bicarbonate and with water, in that order, after which they weredried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography through 40 gof silica gel and by medium pressure liquid chromatography using a LobarB column using mixtures of methylene chloride and ethyl acetate rangingfrom 9:1 to 4:1 by volume as eluent, to give 1.368 g of the titlecompound as a yellow powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.75-3.30(2H, multiplet); 3.40-3.70 (4H, multiplet); 3.83, 3.846 & 3.850(together 15H, each singlet); 6.53 & 6.55 (together 3H, each singlet);6.80-6.95 (4H, multiplet); 7.15-7.35 (4H, multiplet).

Mass spectrum (m/z): 562 (M⁺); 529; 455; 367.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1630, 1605, 1585,1510, 1460, 1420, 1330, 1280, 1170, 1125.

EXAMPLE 67

1-[3,3-Bis(4-methoxyphenyl)thioacryloyl]-4-[3,4,5-trimethoxy(thiobenzoyl)]piperazine

A procedure similar to that described in Example 65 was repeated, butusing 0.790 g of1-[3,3-Bis(4-methoxyphenyl)thioacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine(prepared as described in Example 66), to give 0.792 g of the titlecompound as a yellow powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.99, 3.46,3.56, 3.72, 4.27 & 4.37 (together 8H, 6 broad singlets); 3.82, 3.83 &3.85 (together 15H, each singlet); 6.39 & 6.46 (together 2H, eachsinglet); 6.51 & 6.55 (together 1H, each singlet); 6.80-6.95 (4H,multiplet); 7.10-7.37 (4H, multiplet).

Mass spectrum (m/z): 578 (M⁺); 545; 513; 367.

Infrared Absorption Spectrum (CDCl₃) ν_(max) cm⁻¹ : 1605, 1580, 1510,1460, 1425, 1335, 1280, 1170, 1125.

Elemental analysis: Calculated for C₃₁ H₃₄ N₂₀ O₅ S₂ : C, 69.34%; H,5.92%; N, 4.84%; S, 11.08%. Found: C, 64.21%; H, 6.19%; N, 4.64%; S,10.98%.

EXAMPLE 68

1-[3,3-Bis(3-chlorophenyl)acryloyl]-4-(3,4-dimethoxybenzoyl)piperazine

0.44 ml of diphenylphosphoryl azide and 0.545 g of1-[3,3-bis(3-chlorophenyl)acryloyl]piperazine (prepared as described inPreparation 111) were added to 10 ml of a methylene chloride solutioncontaining 0.25 g of 3,4-dimethoxybenzoic acid and 0.38 ml oftriethylamine, and the reaction mixture was stirred for 16 hours at roomtemperature. At the end of this time, the mixture was washed with 10%w/v aqueous hydrochloric acid, with a saturated aqueous solution ofsodium bicarbonate and with water, in that order, after which it wasdried over anhydrous sodium sulfate. The solvent was then removed bydistillation under reduced pressure, and the resulting residue waspurified by medium pressure chromatography using two Lobar B columnseluted with mixtures of hexane and ethyl acetate ranging from 1:2 to 1:4by volume, to give 0.682 g of the title compound as a white powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.90-3.70(8H, multiplet); 3.89 (3H, singlet); 3.90 (3H, singlet); 6.36 (1H,singlet); 6.85 (1H, doublet, J=7.81 Hz); 6.92 (1H, doublet of doublets,J=7.81 & 1.47 Hz); 6.95 (1H, doublet, J=1.47 Hz); 7.10-7.20 (2H,multiplet); 7.24-7.42 (6H, multiplet).

Mass Spectrum (m/z): 524 (M⁺, ³⁵ Cl), 359, 275, 249, 165.

EXAMPLE 69

1-[3,3-Bis(3-chlorophenyl)acryloyl]-4-(4-methoxybenzoyl)piperazine

0.25 g of p-methoxybenzoyl chloride were added to 10 ml of a methylenechloride solution containing 0.529 g of1-[3,3-bis(3-chlorophenyl)acryloyl]piperazine (prepared as described inPreparation 111) and 0.41 ml of triethylamine, whilst ice-cooling, andthe mixture was stirred at room temperature for 1 hour. The mixture wasthen worked up and purified as described in Example 68 to give 0.682 gof the title compound as a powder.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.90-3.70(8H, multiplet); 3.83 (3H, singlet); 6.36 (1H, singlet); 6.90 (1H,doublet of multiplets, J=8.79 Hz); 7.10-7.19 (2H, multiplet); 7.24-7.42(8H, multiplet).

Mass Spectrum (m/z): 494 (M⁺, ³⁵ Cl), 359, 275, 219, 135.

Elemental analysis: Calculated for C₂₇ H₂₄ N₂ O₃ Cl₂ : C, 65.46%; H,4.88%; N, 5.65%; Cl, 14.31%. Found: C, 65.19%; H, 5.12%; N, 5.64%; Cl,14.55%.

EXAMPLE 70

1-[(Z)-3-(3-Propoxyphenyl)-3-chlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 123, as a powder, in a yieldof 90%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.02(3H,t,J=7.33 Hz), 1.70-1.90(2H,m), 2.80-3.70(8H,m), 3.86(9H,s),3.89(2H,t,J=6.84 Hz), 6.34(1H,s), 6.56(2H,s), 6.76-6.85(2H,m),6.87-6.94(1H,m), 7.16-7.40(5H,m).

Mass Spectrum (m/z):578(M⁺,³⁵ Cl); 383; 299; 279; 257; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻ 1: 1625, 1600, 1585,1460, 1420, 1330, 1125.

EXAMPLE 71

1-[(Z)-3-(4-Propoxyphenyl)-3-(3-chlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 126, as a powder, in a yieldof 78%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.04(3H,t,J=7.32 Hz), 1.75-1.90(2H,m), 3.00-3.70(8H,m), 3.85(9H,m),3.95(2H,t,J=6.35 Hz), 6.28(1H,s), 6.56(2H,s), 6.85(2H,dm,J=8.79 Hz),7.18(2H,dm,J=8.79 Hz), 7.18-7.22(1H,m), 7.26-7.40(3H,m).

Mass Spectrum (m/z): 578(M⁺,³⁵ Cl); 535; 515; 383; 299; 279; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻ 1: 1630, 1610, 1590,1510, 1460, 1425, 1330, 1130.

EXAMPLE 72

1-[(Z)-3-(3-Methoxyphenyl)-3-(2-chlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 129, as a powder, in a yieldof 77%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:3.00-3.70(8H,m), 3.78(3H,s), 3.86(9H,s), 6.58(2H,s), 6.61(1H,s),6.76-6.80(1H,m), 6.80-6.91(2H,m), 7.21-7.44(5H,m).

Mass Spectrum (m/z): 550(M⁺,³⁵ Cl); 515; 271; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻ 1: 1630, 1590, 1465,1425, 1330, 1290, 1130.

EXAMPLE 73

1-[(Z)-3-(4-Methoxyphenyl)-3-(3-bromophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 132, as a powder, in a yieldof 76%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:2.80-3.70(8H,m), 3.83(3H,s), 3.86(9H,s), 6.28(1H,s), 6.57(2H,s),6.87(2H,dm, J=8.79 Hz), 7.20(2H,dm,J=8.79 Hz), 7.23-7.30(2H,m),7.40-7.46(1H,m), 7.48-7.57(1H,m).

Mass Spectrum (m/z): 594(M⁺,⁷⁹ Br); 399; 315; 279; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻ 1: 1630, 1610, 1590,1515, 1475, 1430, 1335, 1180, 1130.

EXAMPLE 74

1-[(Z)-3-(4-Methoxyphenyl)-3-(3-fluorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 136, as a powder, in a yieldof 76%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:2.80-3.70(8H,m), 3.83(3H,s), 3.85(9H,s), 6.28(1H,s), 6.56(2H,s),6.86(2H,dm, J=8.79 Hz), 6.94-7.03(1H,m), 7.04-7.13(2H,m),7.20(2H,dm,J=8.79 Hz), 7.35(1H,ddd,J=7.81,7.81,5.86 Hz).

Mass Spectrum (m/z): 535(M⁺); 339; 279; 255; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻ 1: 1630, 1610, 1590,1515, 1465, 1430, 1335, 1180, 1130.

Example 75

1-[(Z)-3-(4-Methoxyphenyl)-3-(3-trifluoromethylphenyl)acryloxyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 140, as a powder, in a yieldof 79%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:2.80-3.70(8H,m), 3.83(3H,s), 3.846(6H,s), 3.851(3H,s), 6.36(1H,s),6.56(2H,s), 6.87(2H,dm,J=8.79 Hz), 7.19(2H,dm,J=8.79 Hz),7.45-7.58(3H,m), 7.62-7.69(1H,m).

Mass Spectrum (m/z):584(M⁺); 516; 389; 305; 279; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1630, 1605, 1590,1510, 1460, 1425, 1320, 1180, 1130.

EXAMPLE 76

1-[(E)-3-(3-Propoxyphenyl)-3-phenylacryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 143, as a powder, in a yieldof 89%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.02(3H,t,J=7.32 Hz), 1.70-1.90(2H,m), 2.70-3.70(8H,m), 3.84(6H,s),3.85(3H,s), 3.88(2H,t,J=6.35 Hz), 6.30(1H,s), 6.53(2H,s),6.78-6.94(3H,m), 7.19-7.40(6H, m).

Mass Spectrum (m/z): 544(M⁺); 515; 501; 349; 279; 265; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻ 1: 1630, 1590, 1460,1425, 1330, 1280, 1130.

EXAMPLE 77

1-[(Z)-3-(4-Methoxyphenyl)-3-(3,5-dichlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 147, as a powder, in a yieldof 88%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:3.00-3.70(8H,m), 3.83(3H,s), 3.86(9H,s), 6.33(1H,s), 6.59(2H,s),6.88(2H,dm, J=8.78 Hz), 7.17(2H,d,J=1.95 Hz), 7.20(2H,dm,J=8.78 Hz),7.38(1H,t, J=1.95 Hz).

Mass Spectrum (m/z): 584(M⁺, ³⁵ Cl); 389; 305; 279; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1630, 1605, 1590,1560, 1510, 1460, 1420, 1330, 1180, 1130.

EXAMPLE 78

1-[(Z)-3-(4-Methoxyphenyl)-3-(2,4-dichlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 150, as a powder, in a yieldof 93%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:3.00-3.80(8H,m), 3.81(3H,s), 3.86(9H,s), 6.59(1H,s), 6.61(2H,s),6.85(2H,dm, (J=8.79 Hz), 7.16(2H,dm,J=8.79 Hz), 7.25(1H,d,J=8.30 Hz),7.30(1H,dd,J=8.30, 1.95 Hz), 7.44(1H,d,J=1.95 Hz).

Mass Spectrum (m/z): 584(M⁺, ³⁵ Cl); 549; 305; 279; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1630, 1610, 1590,1515, 1465, 1415, 1335, 1180, 1130.

EXAMPLE 79

1-[(Z)-3-(4-Methoxyphenyl)-3-(2.6-dichlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 152, in a yield of 85%.Melting point (solvent)=162°-164° C. (CH₂ Cl₂ -hexane)

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:3.40-3.80(8H,m), 3.82(3H,s), 3.86(9H,s), 6.62(2H,s), 6.78(1H,s),6.87(2H,dm, J=6.83 Hz), 7.20-7.30(3H,m), 7.32-7.42(2H,m).

Mass Spectrum (m/z): 584(M⁺); 549; 305; 279; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1630, 1605, 1590,1510, 1460, 1420, 1330, 1180, 1130.

EXAMPLE 80

1-[(Z)-3-(4-Methoxyphenyl)-3-(2,5-dichlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 154, as a powder, in a yieldof 85%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:3.10-3.80(8H,m), 3.82(3H,s), 3.86(9H,s), 6.60(1H,s), 6.61(2H,s),6.86(2H,dm, J=8.79 Hz), 7.18(2H,dm,J=8.79 Hz), 7.26-7.38(3H,m).

Mass Spectrum (m/z): 584(M⁺,³⁵ Cl); 549; 533; 305; 279; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1630, 1605, 1585,1510, 1460, 1420, 1330, 1175, 1130.

EXAMPLE 81

1-[(Z)-3-(4-Methoxyphenyl)-3-(2,3-dichlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 156, in a yield of 89%.Melting point(solvent)=119°-122° C. (CH₂ Cl₂ -hexane)

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.20-3.80(8H,m), 3.81(3H,s), 3.86(9H,s), 6.58(1H,br,s), 6.60(2H,s),6.85(2H,dm,J=8.79 Hz), 7.17(2H,dm,J=8.79 Hz), 7.23-7.31(2H,m),7.46-7.53(1H,m).

Mass Spectrum (m/z): 584(M⁺,³⁵ Cl); 549; 305; 279; 179.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1630, 1605, 1585,1510, 1460, 1420, 1330, 1280, 1175, 1130.

EXAMPLE 82

1-[(Z)-3-(4-Methoxyphenyl)-3-(3,5-dimethylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 159, as a powder, in a yieldof 75%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 2.29(6H,s),2.60-3.70(8H,m), 3.82(3H,s), 3.846(6H,s), 3.850(3H,s), 6.17(1H,s), 6.54(2H,s), 6.85(2H,dm,J=8.79 Hz), 6.88(2H,br,s), 7.01(1H,br,s), 7.21(2H,dm,J=8.79 Hz).

Mass Spectrum (m/z): 544(M⁺); 349; 279; 265; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1625, 1605, 1590,1505, 1460, 1425, 1330, 1175, 1130.

EXAMPLE83

1-[(Z)-3-(4-Ethylphenyl)-3-(3-chlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 164, as a powder, in a yieldof 78%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.25(3H,t,J=7.81 Hz), 2.67(2H,q,J=7.81 Hz), 2.80-3.70(8H,m), 3.85(9H,s),6.33(1H,s), 6.56(2H,s), 7.14-7.23(5H,m), 7.25-7.29(1H,dd,J=7.82,7.82Hz), 7.37(1H,ddd,J=7.82,1.47,1.47 Hz).

Mass Spectrum (m/z): 548(M⁺); 353; 279; 269; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1630, 1590, 1465,1430, 1235, 1130, 985.

EXAMPLE 84

1-[(Z)-3-(4-Methoxyphenyl)-3-(3,5-di-trifluoromethylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 167, as a powder, in a yieldof 77%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.20-3.70(8H,m), 3.84(3H,s), 3.86(9H,s), 6.28(1H,s), 6.59(2H,s), 6.90(2H,dm,J=8.79 Hz), 7.17(2H,dm,J=8.79 Hz), 7.70-7.74(2H,m), 7.88-7.92(1H,m).

Mass Spectrum (m/z): 652(M⁺); 457; 373; 279; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1630, 1610, 1590,1515, 1460, 1425, 1330, 1280, 1180, 1130.

EXAMPLE 85

1-[(Z)-3-(4-Ethoxyphenyl)-3-(3,5-dichlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 171, as a powder, in a yieldof 82%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.43(3H,t,J=6.84 Hz), 3.20-3.70(8H,m), 3.86(9H,s), 4.05(2H,q,J=6.84 Hz),6.33(1H,s), 6.59(2H,s), 6.86(2H,dm,J=8.79 Hz), 7.166(2H,d,J=1.95 Hz),7.167(2H,dm, J=8.79 Hz), 7.38(1H,t,J=1.95 Hz).

Mass Spectrum (m/z): 598(M⁺); 403; 319; 279; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1630, 1605, 1590,1510, 1460, 1420, 1330, 1220, 1175, 1130.

EXAMPLE 86

1-[(Z)-3-(4-Ethylphenyl)-3-(3,5-dichlorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 175, as a powder, in a yieldof 91%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.25(3H,t,J=7.32 Hz), 2.67(2H,q,J=7.32 Hz), 3.00-3.75(8H,m), 3.86(9H,s),6.38(1H,s), 6.59(2H,s), 7.10-7.26(4H,m), 7.17(2H,d,J=1.95 Hz),7.38(1H,t,J=1.95 Hz).

Mass Spectrum (m/z): 582(M⁺); 387; 303; 279; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1630, 1590, 1560,1460, 1425, 1330, 1220, 1130.

EXAMPLE 87

1-[(Z)-3-(4-Methoxyphenyl)-3-(3,5-difluorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 179, as a powder, in a yieldof 95%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.05-3.75(8H,m), 3.83(3H,s), 3.86(9H,s), 6.33(1H,s), 6.59(2H,s), 6.77-6.91(3H,m),6.87(2H,dm,J=8.79 Hz), 7.19(2H,dm,J=8.79 Hz).

Mass Spectrum (m/z): 552(M⁺); 357; 279; 273; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1625, 1610, 1595,1515, 1465, 1430, 1335, 1180, 1130.

EXAMPLE 88

1-[(Z)-3-(4-Ethoxyphenyl)-3-(3-fluorophenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 185, as a powder, in a yieldof 94%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.42(3H,t,J=6.83 Hz), 2.70-3.70(8H,m), 3.85(9H,s), 4.05(2H,q,J=6.83 Hz),6.28(1H,s), 6.56(2H,s), 6.85(2H,dm,J=8.79 Hz), 6.93-7.03(1H,m),7.03-7.13(2H,m), 7.19 (2H,dm,J=8.79 Hz), 7.35(1H,ddd,J=

Mass Spectrum (m/z): 548(M⁺); 533; 519; 353; 279; 269; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1625, 1605, 1585,1505, 1460, 1420, 1330, 1170, 1125.

EXAMPLE 89

1-[(Z)-3-(4-Methoxyphenyl)-3-(3-chloro-5-methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 189, as a powder, in a yieldof 91%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 2.33(3H,s),2.70-3.70(8H,m), 3.83(3H,s), 3.86(9H,s), 6.25(1H,s) 6.57(2H,s), 6.86(2H,dm,J=8.79 Hz), 6.93-7.11(2H,m), 7.14-7.25(1H,m), 7.20(2H,dm,J=8.79Hz).

Mass Spectrum (m/z): 564(M⁺,³⁵ Cl); 549; 369; 285; 279; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻ 1: 1625, 1600, 1585,1510, 1460, 1420, 1330, 1170, 1125.

EXAMPLE 90

1-[(Z)-3-(4-Ethoxyphenyl)-3-(3-chloro-5-methylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)piperazine

Prepared from the compound of Preparation 193, as a powder, in a yieldof 92%.

Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl₃) δ ppm: 1.40(3H,t,J=7Hz), 2.32(3H,s), 2.90-3.75(8H,m), 3.85(9H,s), 4.04(2H,q,J=7 Hz), 6.26(1H,s), 6.59(2H,s), 6.80-7.40(3H,m), 6.86(2H,dm,J=9 Hz), 7.22(2H,q,J=9Hz).

Mass Spectrum (m/z): 578(M⁺,³⁵ Cl); 563; 383; 299; 279; 195.

EXAMPLE 91

1-[(Z)-3-(2-Chlorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(4-acetoxy-3,5-dimethoxybenzoyl)piperazine

Following the procedure described in Example 68, but using a compound ofPreparation 196 (0.600 g) and a compound of Preparation 195 (0.936 g),there was obtained the title compound (1.072 g) as a powder.

Melting point:191°-194° C.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 2.34(3H,s),2.70-3.70(8H,m), 3.82(6H,s), 3.83(3H,s), 6.28(1H,s), 6.58(2H,s), 6.87(2H,dm,J=8.79 Hz), 7.16-7.23(3H,m), 7.32(1H,dd,J=7.32, 7.32 Hz),7.37(1H, ddd,J=7.81,1.95,1.95 Hz)

Mass Spectrum (m/z): 578(M⁺,³⁵ Cl); 536; 355; 307; 271; 181.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻ 1: 1770, 1630, 1600,1515, 1460, 1430, 1370, 1340, 1285, 1180, 1135.

EXAMPLE 92

1-[(Z)-3-(2-Chlorophenyl)-3-(4-methoxyphenyl)acryloyl]-4-(3,5-dimethoxy-4-hydroxybenzoyl)piperazine

To a solution of a compound of Example 91 (0.500 g) in methanol (20 ml)was added an aqueous solution saturated with potassium carbonate (10ml), and the resulting mixture was stirred at room temperature for anhour. The reaction mixture was poured into water and extracted thricewith methylenechloride. The combined extract was washed with water,dried and concentrated. The residue was purified by liquidchromatography under medium pressure through two Lobar B columns.Fractions eluted with a 19:1 mixture of ethyl acetate and methanol werecollected and worked up to afford the title compound (0.464 g) as apowder.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.00-3.70(8H,m), 3.83(3H,s), 3.89(6H,s), 5.72(1H,s), 6.61(2H,s), 6.87(2H,dm,J=9.27 Hz), 7.16-7.23(3H,m), 7.31(1H,dd,J=8.30,8.30 Hz), 7.37(1H,ddd,J=8.30,1.95,1.95 Hz).

Mass Spectrum (m/z): 536(M⁺); 356; 355; 271; 265; 181.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻ 1: 3550, 1630, 1605,1510, 1460, 1420, 1365, 1330, 1280, 1180, 1115, 980, 830.

EXAMPLE 93

1-[(Z)-3-(4-Methoxyphenyl)-3-(3-trifluoromethylphenyl)acryloyl]-4-(3,4,5-trimethoxybenzoyl)hexahydro-1H-1,4-diazepine

In a manner similar to that of Example 7, the condensation reaction of acompound of Preparation 140 (0.516 g) with1-(3,4,5-trimethoxybenzoyl)homopiperazine (0.471 g) and the work-up ofthe reaction product were carried out to give the title compound (0.819g) as a powder.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 1.60-2.10(2H,m), 3.20-3.80(8H,m), 3.82(3H,s), 3.83(3H,s), 3.85(3H,s), 3.86(3H,s),6.46(1H,br.s), 6.55(2H,s), 6.81-6.92(2H,m), 7.14-7.25(2H,m), 7.40-7.52(2H,m), 7.52-7.66(2H,m).

Mass Spectrum (m/z): 598(M⁺); 403; 305; 293; 195.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻ 1: 1630, 1610, 1590,1510, 1465, 1420, 1320, 1180, 1130.

PREPARATION 1

(E)- and (Z)-3-Phenyl-3-(2-thienyl)acrylic acids

100 ml of a tetrahydrofuran solution containing 26.30 g of triethylphosphonoacetate were dropped over a period of 15 minutes at 8°-10° C.into 400 ml of a tetrahydrofuran suspension containing 5.63 g of sodiumhydride (as a 55% w/w suspension in mineral oil), in an ice bath. Thereaction solution was then stirred for 1 hour at room temperature, afterwhich 22.08 g of 2-benzoylthiophene were added. The reaction mixture wasthen heated under reflux for 21 hours, poured into 300 ml of water andextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate and the solvent was distilled off under reduced pressure.26.56 g of the resulting oily residue were dissolved in 450 ml ofmethanol, and 150 ml of a 10% w/v aqueous solution of sodium hydroxidewere added thereto. The mixture was then stirred for 2 hours at roomtemperature. At the end of this time, the reaction solution was pouredinto 500 ml of water and washed with methylene chloride. Sufficientaqueous hydrochloric acid was added to the aqueous phase to adjust thepH to a value of 2, and then the mixture was extracted with methylenechloride. The extract was dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography. Elution with a 19:1 byvolume mixture of methylene chloride and methanol gave at first 3.415 gof the less polar isomer A [thought to be the (Z)-isomer, Rf: 0.48(silica gel, developing solvent: a 24:1 volume mixture of methylenechloride and methanol)], and next 0.789 g of the other more polar isomerB [thought to be the (E)-isomer, Rf: 0.35 (silica gel, developingsolvent: a 24:1 by volume mixture of methylene chloride and methanol)].

Isomer A:

Pale brown crystals, melting at 144°-147° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 90 MHz) δ ppm: 6.34 (1H,singlet); 6.80-7.10 (2H, multiplet); 7.15-7.50 (6H, multiplet); 9.93(1H, broad singlet).

Mass spectrum (m/z): 230 (M⁺).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1685, 1610, 1595.

Elemental analysis: Calculated for C₁₃ H₁₀ O₂ S: C. 67.80%; H, 4.38%; S,13.92%. Found: C, 67.71%; H, 4.12%; N, 13.88%.

Isomer B:

Pale brown crystals, melting at 152°-155° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 90 MHz) δ ppm: 6.18 (1H,singlet); 6.95-7.15 (1H, multiplet); 7.15-7.55 (7H, multiplet); 10.66(1H, broad singlet).

Mass spectrum (m/z): 230 (M⁺).

Infrared Absorption Spectrum (CDCl₃) ν_(max) cm⁻¹ : 1690, 1595.

PREPARATION 2

Ethyl (E)- and (Z)-3-phenyl-3-(4-pyridyl)acrylates

100 ml of a tetrahydrofuran solution containing 26.92 g of triethylphosphonoacetate were dropped over a period of 20 minutes into 400 ml ofa tetrahydrofuran suspension containing 5.76 g of sodium hydride (as a55% w/w suspension in mineral oil), at 8°-10° C. in an ice bath. Thereaction solution was then stirred for 1 hour at room temperature, afterwhich 22.00 g of 4-benzoylpyridine were added. After the mixture hadbeen stirred for a further 3 hours, the reaction solution was pouredinto 300 ml of water and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and then the solvent was distilledoff under reduced pressure. The resulting residue was purified by silicagel column chromatography. Elution with mixtures of hexane and methylenechloride ranging from 3:1 to 1:1 by volume gave at first 10.047 g of theless polar isomer C [thought to be the (Z)-isomer, Rf: 0.63 (silica gel,developing solvent: a 49:1 by volume mixture of methylene chloride andmethanol)], and next elution with mixtures of hexane and methylenechloride ranging from 1:1 to 0:1 by volume gave 16.603 g of the othermore polar isomer D [thought to be the (E)-isomer, Rf: 0.55 (silica gel,developing solvent: a 49:1 by volume mixture of methylene chloride andmethanol)].

Isomer C:

Colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 90 MHz) δ ppm: 1.11 (3H,triplet, J=7.5 Hz); 4.07 (2H, quartet, J=7.5 Hz); 6.48 (1H, singlet);7.05-7.55 (7H, multiplet). 8.40-8.90 (2H, multiplet).

Mass spectrum (m/z): 253 (M⁺), 208 (M⁺ --C₂ H₅ O).

Infrared Absorption Spectrum (CDCl₃) ν_(max) cm⁻¹ : 1720.

Elemental analysis: Calculated for C₁₆ H₁₅ NO₂ : C, 75.87%; H, 5.97%; S,5.53%. Found: C, 75.91%; H, 6.26%; N, 5.48%.

Isomer D:

Colorless crystals, melting at 101°-102° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 90 MHz) δ ppm: 1.12 (3H,triplet, J=7.2 Hz); 4.05 (2H, quartet, J=7.5 Hz); 6.46 (1H, singlet);7.05-7.50 (7H, multiplet); 8.50-8.85 (2H, multiplet).

Mass spectrum (m/z): 253 (M⁺), 208 (M⁺ --C₂ H₅ O).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1715.

Elemental analysis: Calculated for C₁₆ H₁₅ NO₂ : C, 75.87%; H, 5.97%; S,5.53%. Found: C, 75.86%; H, 5.86%; N, 5.59%.

PREPARATION 3

(E)-3-Phenyl-3-(4-pyridyl)acrylic acid

20 ml of a 10% w/v aqueous solution of sodium hydroxide were added to 35ml of a methanol solution containing 3.41 g of ethyl(E)-3-phenyl-3-(4-pyridyl)acrylate (prepared as described in Preparation2), and the mixture was stirred for 1 hour at room temperature. At theend of this time, the reaction solution was poured into 50 ml of waterand washed with methylene chloride. Sufficient hydrochloric acid wasadded to the aqueous phase to adjust the pH to a value of 2.8. Theresulting precipitate was collected, giving 2.131 g of the titlecompound, as a white powder, melting at 239°-241° C.

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide,90 MHz) δ ppm: 6.51 (1H, singlet); 7.15-7.55 (7H, multiplet); 8.45-8.80(2H, multiplet).

Mass spectrum (m/z): 255 (M⁺); 180 (M⁺ --COOH).

Infrared Absorption Spectrum (Nujol--trade mark) ν_(max) cm⁻¹ : 1697;1625; 1602.

PREPARATIONS 4 to 103

General Synthesis of 3,3-Diphenylacrylic Acid Derivatives According toHeck's Reaction

This follows essentially the same method as that reported by Heck et al.[J. Org. Chem. 43, 2952 (1978)], in which a coupling reaction of an(E)-acrylic acid ester having a substituted group, R¹, at its 3-positionwith an iodine compound having a substituted group, R², was conducted. Amixture of 20 mmole of an (E)-acrylic acid ethyl ester having R¹ at its3-position, 30 mmole of an aryl iodide represented by the generalformula R² --I, 4.17 ml of triethylamine, 0.270 g of palladium acetateand 8 ml of acetonitrile was put into a sealed tube, and heated for 18hours in an oil bath at 100° C. The mixture was stood to allow it tocool, after which it was diluted with 30 ml of ethyl acetate, and thenwashed with 10% w/v aqueous hydrochloric acid, with a saturated aqueoussolution of sodium bicarbonate and with a saturated aqueous solution ofsodium chloride, in that order. The organic phase was dried andcondensed by evaporation under reduced pressure. The residue wassubjected to flash column chromatography using silica gel (about 400Tyler mesh, 400 g), and medium pressure liquid chromatography using aLobar C column (Type Si-60). Elution with mixtures of methylenechloride, diethyl ether and hexane ranging from 1:1:5 to 1:1:4 by volumegave separately the (E)-isomer and the (Z)-isomer of a 3,3-disubstitutedethyl acrylate. Where two isomers were produced, each is mentioned in aseparate Preparation, but the isomer eluted earlier in thechromatographic procedure mentioned above appears in the first of thepair of Preparations. Toluene was employed as the eluent for separationof the isomers of the compounds of Preparations 32/33, and 36/37. Theisolated (E)- or (Z)-3,3-diphenylacrylic acid ethyl ester (4 mmole) wasdissolved in a mixture of 12 ml of dioxane and 12 ml of methanol, and 5ml of a 10% w/v aqueous solution of sodium hydroxide were added forhydrolysis. The reaction mixture was stirred for 18 hours at roomtemperature, and then the solvent was distilled off. The residue wasdiluted with 20 ml of water and washed with ethyl acetate. Sufficient10% w/v aqueous hydrochloric acid was added to the aqueous phase toadjust the pH to a value of 2, and then the mixture was extracted twicewith methylene chloride. The combined methylene chloride extracts werewashed with water and then dried over anhydrous sodium sulfate. Thedesired 3,3-disubstituted acrylic acid was obtained as a solid. Theresults are summarized below.

The ester compounds of Preparations 96 and 97 could not, however, beseparated by the method described above. Accordingly, they wereseparated by the following procedure:

The mixture of the compounds of Preparations 96 and 97 was hydrolized asdescribed above. The mixture of the acid compounds thus obtained wasthen washed with methylene chloride, and the insoluble material wasrecrystallized from a mixture of diethyl ether and tetrahydrofuran, togive the compound of Preparation 96 (believed to be the E-isomer). Themethylene chloride washings were condensed by distillation under reducedpressure, and the residue was recrystallized from a mixture of methylenechloride and hexane, to give the compound of Preparation 97 (believed tobe the Z-isomer).

PREPARATION 4

Ethyl (E)-3-(3,4-dimethoxyphenyl)cinnamate

Prepared as an oil in a yield of 14%

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.10 (3H,triplet, J=7.32 Hz); 3.82 (3H, singlet); 3.88 (3H, singlet); 4.04 (2H,quartet, J=7.32 Hz); 6.32 (1H, singlet); 6.74-6.84 (2H, multiplet); 6.89(1H, broad singlet); 7.16-7.25 (2H, multiplet); 7.34-7.42 (2H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1705, 1595, 1580,1510, 1465, 1160, 1135.

Mass Spectrum (m/z): 312 (M⁺), 297, 283, 267, 240.

PREPARATION 5

Ethyl (Z)-3-(3,4-dimethoxyphenyl)cinnamate

Prepared as crystals, melting at 93°-95° C. (after recrystallisationfrom a mixture of diethyl ether and hexane), in a yield of 21%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.16 (3H,triplet, J=7.32 Hz); 3.81 (3H, singlet); 3.92 (3H, singlet); 4.09 (2H,quartet, J=7.32 Hz); 6.29 (1H, singlet); 6.72 (1H, doublet, J=1.95 Hz);6.82 (1H, doublet of doublets, J=830 & 1.95 Hz); 6.88 (1H, doublet,J=8.30 Hz); 7.30-7.14 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻ : 1710, 1605, 1585,1515, 1465, 1445, 1160, 1135.

Mass Spectrum (m/z): 312 (M⁺), 297, 283, 267, 240.

PREPARATION 6

(E)-3-(3,4-Dimethoxyphenyl)cinnamic acid

Prepared as crystals, melting at 178°-181° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 98%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.81 (3H,singlet); 3.88 (3H, singlet); 6.28 (1H, singlet); 6.75-6.83 (2H,multiplet); 6.86 (1H, broad singlet); 7.17-7.25 (2H, multiplet;7.33-7.43 (3H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1595, 1515, 1260, 1135.

Mass Spectrum (m/z): 284 (M⁺), 269, 267, 239.

PREPARATION 7

(Z)-3-(3,4-Dimethoxyphenyl)cinnamic acid

Prepared as crystals, melting at 162°-164° C. (after recrystallisationfrom a mixture of diethyl ether and hexane), in a yield of 99%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.80 (3H,singlet); 3.92 (3H, singlet); 6.26 (1H, singlet); 6.75 (1H, doublet,J=1.95 Hz); 6.80 (1H, doublet of doublets, J=8.30 & 1.95 Hz); 6.87 (1H,doublet, J=8.30 Hz); 7.27-7.43 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1605, 1515, 1255, 1135.

Mass Spectrum (m/z): 284 (M⁺), 269, 267, 239.

PREPARATION 8

Ethyl (E)-3-(3,4,5-trimethoxyphenyl)cinnamate

Prepared as crystals, melting at 119°-121° C. (after recrystallisationfrom a mixture of diethyl ether, methylene chloride and hexane), in ayield of 19%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.11 (3H,triplet, J=7.32 Hz); 3.77 (6H, singlet); 3.87 (3H, singlet); 4.05 (2H,quartet, J=7.32 Hz); 6.32 (1H, singlet); 6.51 (2H, singlet), 7.18-7.24(2H, multiplet); 7.35-7.41 (3H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1615, 1580,1500, 1460, 1415, 1160, 1125.

Mass Spectrum (m/z): 342 (M⁺), 327, 313, 299, 297.

PREPARATION 9

Ethyl (Z)-3-(3,4,5-trimethoxyphenyl)cinnamate

Prepared as crystals, melting at 96°-98° C. (after recrystallisationfrom a mixture of methylene chloride and diethyl ether), in a yield of35%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.14 (3H,triplet, J=7.33 Hz); 3.80 (6H, singlet); 3.90 (3H, singlet); 4.08 (2H,quartet, J=7.33 Hz); 6.32 (1H, singlet); 6.43 (2H, singlet); 7.31-7.40(5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1610, 1585,1500, 1460, 1410, 1300, 1170, 1125.

Mass Spectrum (m/z): 342 (M⁺), 327, 313, 299, 297.

PREPARATION 10

(E)-3-(3,4,5-Trimethoxyphenyl)cinnamic acid

Prepared as crystals, melting at 202°-206° C. (after recrystallisationfrom a mixture of diethyl ether and methylene chloride), in a yield of100%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.76 (6H,singlet); 3.87 (3H, singlet); 6.30 (1H, singlet); 6.49 (2H, singlet);7.19-7.25 (2H, multiplet); 7.35-7.41 (3H, multiplet).

Infrared Absorption Spectrum (KBr) ν_(max) cm⁻¹ : 2400-3400 (broad),1688, 1610, 1578, 1502, 1241, 1200, 1129.

Mass Spectrum (m/z): 314 (M⁺), 299.

PREPARATION 11

(Z)-3-(3,4,5-Trimethoxyphenyl)cinnamic acid

Prepared as crystals, melting at 203°-205° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 100%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.78 (6H,singlet); 3.91 (3H, singlet); 6.30 (1H, singlet); 6.44 (2H, singlet);7.28-7.43 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1610, 1580, 1500, 1460, 1410, 1365, 1125.

Mass Spectrum (m/z): 314 (M⁺), 299.

PREPARATION 12

Ethyl (E)-3-(3-methoxy-4-propoxyphenyl)cinnamate

Prepared as crystals, melting at 66°-68° C. (after recrystallisationfrom hexane), in a yield of 24%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.03 (3H,triplet, J=7.32 Hz); 1.10 (3H, triplet, J=7.33 Hz); 1.80-1.95 (2H,multiplet); 3.81 (3H, singlet); 3.98 (2H, triplet, J=6.84 Hz); 4.03 (2H,quartet, J=7.33 Hz); 6.31 (1H, singlet); 6.77 (1H, singlet); 6.78 (1H,singlet); 6.89 (1H, singlet); 7.16-7.25 (2H, multiplet); 7.35-7.45 (3H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1600, 1520,1470, 1375, 1260, 1160, 1140.

Mass Spectrum (m/z): 340 (M⁺), 298, 269, 253, 226.

PREPARATION 13

Ethyl (Z)-3-(3-methoxy-4-propoxyphenyl)cinnamate

Prepared as an oil in a yield of 37%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.05 (3H,triplet, J=7.32 Hz); 1.15 (3H, triplet, J=7.32 Hz); 1.80-2.00 (2H,multiplet); 3.79 (3H, singlet); 4.01 (2H, triplet, J=6.83 Hz); 4.08 (2H,quartet, J=7.32 Hz); 6.27 (1H, singlet); 6.72 (1H, doublet, J=1.95 Hz);6.78 (1H, doublet of doublets, J=8.30 & 1.95 Hz); 6.87 (1H, doublet,J=8.30 Hz); 7.30-7.42 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1610, 1515,1470, 1375, 1260, 1170, 1140.

Mass Spectrum (m/z): 340 (M⁺), 298, 269, 253, 226.

PREPARATION 14

(E)-3-(3-Methoxy-4-propoxyphenyl)cinnamic acid

Prepared as crystals, melting at 147°-150° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 94%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.03 (3H,triplet, J=7.33 Hz); 1.75-2.00 (2H, multiplet); 3.79 (3H, singlet); 3.98(2H, triplet, J=6.84 Hz); 6.28 (1H, singlet); 6.73-6.80 (2H, multiplet);6.85 (1H, broad singlet); 7.15-7.25 (2H, multiplet). 7.33-7.40 (3H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1610, 1595, 1580, 1510, 1465, 1260, 1180, 1135.

Mass Spectrum (m/z): 312 (M⁺), 270, 253, 225.

PREPARATION 15

(Z)-3-(3-Methoxy-4-propoxyphenyl)cinnamic acid

Prepared as crystals, melting at 139°-142° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 93%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.06 (3H,triplet, J=7.33 Hz); 1.80-2.00 (2H, multiplet); 3.79 (3H, singlet); 4.01(2H, triplet, J=6.84 Hz); 6.24 (1H, singlet); 6.29-6.79 (2H, multiplet);6.85 (1H, doublet of doublets, J=8.33 & 1.47 Hz); 7.25-7.45 (5H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1600, 1575, 1510, 1465, 1445, 1410, 1250, 1130.

Mass Spectrum (m/z): 312 (M⁺), 270, 253, 225.

PREPARATION 16

Ethyl (E)-3-(3,4-dipropoxyphenyl)cinnamate

Prepared as an oil in a yield of 16%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.01 (3H,triplet, J=7.33 Hz); 1.03 (3H, triplet, J=7.33 Hz); 1.10 (3H, triplet,J=7.33 Hz); 1.70-1.95 (4H, multiplet); 3.90 (2H, triplet, J=6.83 Hz);3.96 (2H, triplet, J=6.83 Hz) 4.03 (2H, quartet, J=7.33 Hz); 6.30 (1H,singlet); 6.72-6.80 (2H, multiplet); 6.90 (1H, broad singlet); 7.15-7.25(2H, multiplet). 7.30-7.45 (3H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1705, 1595, 1510,1470, 1370, 1260, 1160, 1130.

Mass Spectrum (m/z): 368 (M⁺), 326, 323, 284.

PREPARATION 17

Ethyl (Z)-3-(3,4-dipropoxyphenyl)cinnamate

Prepared as an oil in a yield of 25%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.00 (3H,triplet, J=7.32 Hz); 1.06 (3H, triplet, J=7.32 Hz); 1.15 (3H, triplet,J=7.32 Hz); 1.70-1.95 (4H, multiplet); 3.89 (2H, triplet, J=6.84 Hz);4.00 (2H, triplet, J=6.84 Hz) 4.08 (2H, quarter, J=7.32 Hz); 6.26 (1H,singlet); 6.73 (1H, doublet, J=1.95 Hz); 6.77 (1H, doublet of doublets,J=8.30 & 1.95 Hz); 6.86 (1H, doublet, J=8.30 Hz); 7.25-7.40 (5H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1605, 1510,1470, 1445, 1370, 1260, 1160, 1130.

Mass Spectrum (m/z): 3.68 (M⁺), 326, 323, 284.

PREPARATION 18

(E)-3-(3,4-Dipropoxyphenyl)cinnamic acid

Prepared as crystals, melting at 102°-103° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 92%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.00 (3H,triplet, J=7.32 Hz); 1.03 (3H, triplet, J=7.32 Hz); 1.70-1.95 (4H,multiplet); 3.89 (2H, triplet, J=6.83 Hz); 3.96 (2H, triplet, J=6.84Hz); 6.26 (1H, singlet); 6.74 (1H, doublet of doublets, J=8.30 & 1.96Hz); 6.78 (1H, doublet, J=8.30 Hz); 6.86 (1H, doublet, J=1.96 Hz);7.15-7.25 (2H, multiplet); 7.30-7.40 (3H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1610, 1595, 1580, 1510, 1425, 1260, 1135.

Mass Spectrum (m/z): 340 (M⁺), 298, 256, 239.

PREPARATION 19

(Z)-3-(3,4-Dipropoxyphenyl)cinnamic acid

Prepared as crystals, melting at 120°-123° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 94%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.00 (3H,triplet, J=7.33 Hz); 1.06 (3H, triplet, J=7.32 Hz); 1.70-1.95 (4H,multiplet); 3.89 (2H, triplet, J=6.84 Hz); 4.00 (2H, triplet, J=6.84Hz); 6.23 (1H, singlet); 6.73-6.80 (2H, multiplet); 6.83-6.87 (1H,multiplet); 7.25-7.45 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1610, 1515, 1260, 1135.

Mass Spectrum (m/z): 340 (M⁺), 298, 256, 239.

PREPARATION 20

Ethyl (E)-3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylate

Prepared as crystals, melting at 83°-84° C. (after recrystallisationfrom a mixture of diethyl ether and hexane), in a yield of 14%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.15 (3H,triplet, J=7.32 Hz); 3.84 (3H, singlet); 3.89 (3H, singlet); 4.06 (2H,quartet, J=7.32 Hz); 6.31 (1H, singlet); 6.76 (1H, doublet of doublets,J=8.79 & 1.95 Hz); 6.80 (1H, doublet, J=8.79 Hz); 6.86 (1H, doublet,J=1.95 Hz); 7.15 (2H, doublet of multiplets, J=8.79 Hz); 7.36 (2H,doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1705, 1615, 1595,1580, 1510, 1460, 1370, 1290, 1160, 1135.

Mass Spectrum (m/z): 346 (M⁺, ³⁵ Cl), 317, 301, 274.

PREPARATION 21

Ethyl (Z)-3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylate

Prepared as crystals, melting at 67°-69° C. (after recrystallisationfrom a mixture of diethyl ether and hexane), in a yield of 22%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.16 (3H,triplet, J=7.32 Hz); 3.81 (3H, singlet); 3.91 (3H, singlet); 6.26 (1H,singlet); 6.70 (1H, doublet, J=1.95 Hz); 6.79 (1H, doublet of doublets,J=8.30 & 1.95 Hz); 6.88 (1H, doublet, J=8.30 Hz); 7.12-7.40 (4H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1600, 1590,1515, 1490, 1460, 1255, 1170, 1135.

Mass Spectrum (m/z): 346 (M⁻, ³⁵ Cl), 317, 301, 274.

PREPARATION 22

(E)-3-(4-Chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylic acid

Prepared as crystals, melting at 164°-165° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 85%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.83 (3H,singlet); 3.89 (3H, singlet); 6.29 (1H, singlet); 6.76 (1H, doublet ofdoublets, J=8.30 & 1.95 Hz); 6.80 (1H, doublet, J=8.30 Hz); 6.84 (1H,doublet, J=1.95 Hz); 7.15 (2H, doublet of multiplets, J=8.30 Hz); 7.35(2H, doublet of multiplets, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1610, 1595, 1515, 1465, 1260, 1175, 1135.

Mass Spectrum (m/z): 318 (M⁺), 303, 243.

PREPARATION 23

(Z)-3-(4-Chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylic acid

Prepared as crystals, melting at 188°-190° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 91%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.80 (3H,singlet); 3.92 (3H, singlet); 6.23 (1H , singlet); 6.72 (1H, doublet,J=1.95 Hz); 6.78 (1H, doublet of doublets, J=8.30 & 1.95 Hz); 6.86 (1H,doublet, J=8.30 Hz); 7.23 (2H, doublet of multiplets, J=8.79 Hz); 7.31(2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1605, 1585, 1515, 1490, 1465, 1415, 1255, 1135.

Mass Spectrum (m/z): 318 (M⁺), 303, 243.

PREPARATION 24

Ethyl (Z)-3-(3-chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylate

Prepared as an oil in a yield of 13%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 1.11 (3H,triplet, J=7 Hz); 3.83 (3H, singlet); 3.88 (3H, singlet); 4.06 (2H,quartet, J=7 Hz); 6.35 (1H, singlet); 6.75-7.00 (3H, multiplet);7.00-7.50 (4H, multiplet).

PREPARATION 25

Ethyl (E)-3-(3-chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylate

Prepared as an oil in a yield of 20%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 1.15 (3H,triplet, J=7 Hz); 3.81 (3H, singlet); 3.90 (3H, singlet); 4.08 (2H,quartet, J=7 Hz); 6.29 (1H, singlet); 6.70-7.00 (3H, multiplet);7.10-7.45 (4H, multiplet).

PREPARATION 26

(Z)-3-(3-Chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylic acid

Prepared as crystals, melting at 178°-181° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 90%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.83 (3H,singlet); 3.89 (3H, singlet); 6.30 (1H, singlet); 6.75 (1H, doublet ofdoublets, J=8.30 & 1.95 Hz) 6.80 (1H, doublet, J=8.30 Hz); 6.85 (1H,doublet, J=1.95 Hz); 7.10 (1H, doublet of triplets, J=7.81 & 1.46 Hz);7.20 (1H, triplet, J=1.46 Hz); 7.31 (1H, triplet, J=7.81 Hz); 7.36 (1H,doublet of triplets, J=7.81 & 1.46 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1600, 1590, 1580, 1510, 1460, 1420, 1255, 1140.

Mass Spectrum (m/z): 318 (M⁺,³⁵ Cl), 303.

PREPARATION 27

(Z)-3-(3-Chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylic acid

Prepared as crystals, melting at 158°-160° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 91%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.81 (3H,singlet); 3.92 (3H, singlet); 6.23 (1H, singlet); 6.73 (1H, doublet,J=1.95 Hz); 6.78 (1H, doublet of doublets, J=8.30 & 1.95 Hz); 6.87 (1H,doublet, J=8.30 Hz); 7.15-7.40 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1600, 1580, 1565, 1515, 1460, 1420, 1255, 1135.

Mass Spectrum (m/z): 318 (M⁺, ³⁵ Cl), 303.

PREPARATION 28

Ethyl (E)-3-(4-Chlorophenyl)-3-(2,3-dimethoxyphenyl)acrylate

Prepared as crystals, melting at 82°-84° C. (after recrystallisationfrom hexane), in a yield of 4%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.17 (3H,triplet, J=7.32 Hz); 3.39 (3H, singlet); 3.84 (3H, singlet); 4.10 (2H,quartet, J=7.32 Hz); 6.16 (1H, singlet); 6.82 (1H, doublet of doublets,J=8.30 & 1.46 Hz); 6.93 (1H, doublet of doublets, J=8.30 & 1.46 Hz);7.04 (1H, triplet, J=8.30 Hz); 7.20 (2H, doublet of multiplets, J=8.79Hz); 7.29 (2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1715, 1620, 1600,1580, 1495, 1475, 1430, 1370, 1260, 1170.

Mass Spectrum (m/z): 346 (M⁺, ³⁵ Cl), 315, 301, 287.

PREPARATION 29

Ethyl (Z)-3-(4-Chlorophenyl)-3-(2,3-dimethoxyphenyl)acrylate

Prepared as crystals, melting at 90°-92° C. (after recrystallisationfrom hexane), in a yield of 37%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.11 (3H,triplet, J=7.32 Hz); 3.58 (3H, singlet); 3.89 (3H, singlet); 4.04 (2H,quartet, J=7.32 Hz); 6.43 (1H, singlet); 6.69 (1H, doublet of doublets,J=8.30 & 1.47 Hz); 6.95 (1H, doublet of doublets, J=8.30 & 1.47 Hz);7.08 (1H, triplet, J=8.30 Hz); 7.28 (4H, singlet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1720, 1625, 1590,1580, 1495, 1480, 1430, 1370, 1260, 1170.

Mass Spectrum (m/z): 346 (M⁺, ³⁵ Cl), 315, 301, 287.

PREPARATION 30

(E)-3-(4-Chlorophenyl)-3-(2,3-dimethoxyphenyl)acrylic acid

Prepared as crystals, melting at 129°-131° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 98%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.39 (3H,singlet); 3.84 (3H, singlet); 6.16 (1H, singlet); 6.79 (1H, doublet ofdoublets, J=8.30 & 1.47 Hz); 6.93 (1H, doublet of doublets, J=8.30 &1.47 Hz); 7.04 (1H, triplet, J=8.30 Hz); 7.20 (1H, doublet ofmultiplets, J=8.79 Hz); 7.28 (2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1620, 1600, 1580, 1495, 1475, 1425. 1260.

Mass Spectrum (m/z): 318 (M⁺, ³⁵ Cl), 287.

PREPARATION 31

(Z)-3-(4-Chlorophenyl)-3-(2,3-dimethoxyphenyl)acrylic acid

Prepared as crystals, melting at 147° C. (after recrystallisation from amixture of methylene chloride and hexane), in a yield of 98%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.57 (3H,singlet); 3.88 (3H, singlet); 6.38 (1H, singlet); 6.67 (1H, doublet ofdoublets, J=7.81 & 1.46 Hz); 6.94 (1H, doublet of doublets, J=7.81 &1.46 Hz); 7.06 (1H, triplet, J=7.81 Hz); 7.20-7.33 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1620, 1590, 1580, 1495, 1480, 1425, 1265.

Mass Spectrum (m/z): 318 (M⁺, ³⁵ Cl), 287.

PREPARATION 32

Ethyl (Z)-3-(4-Chlorophenyl)-3-(4-isobutoxyphenyl)acrylate

Prepared as an oil in a yield of 13%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.02 (6H,doublet, J=6.83 Hz); 1.14 (3H, triplet, J=7.32 Hz); 2.00-2.15 (1H,multiplet); 3.72 (2H, doublet, J=6.35 Hz); 4.05 (2H, quartet, J=7.32Hz); 6.30 (1H, singlet); 6.83 (2H, doublet of multiplets, J=8.79 Hz);7.14 (2H, doublet of multiplets, J=8.79 Hz); 7.20 (2H, doublet ofmultiplets, J=8.79 Hz); 7.35 (2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1605, 1515,1495, 1475, 1375, 1280, 1255, 1170.

Mass Spectrum (m/z): 358 (M⁺, ³⁵ Cl), 313, 302.

PREPARATION 33

Ethyl (E)-3-(4-Chlorophenyl)-3-(4-isobutoxyphenyl)acrylate

Prepared as an oil in a yield of 16%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.03 (6H,doublet, J=6.83 Hz); 1.17 (3H, triplet, J=7.32 Hz); 2.00-2.20 (1H,multiplet); 3.74 (2H, doublet, J=6.35 Hz); 4.09 (2H, quartet, J=7.32Hz); 6.23 (1H, singlet); 6.89 (2H, doublet of multiplets, J=9.28 Hz);7.11 (2H, doublet of multiplets, J=9.28 Hz); 7.22 (2H, doublet ofmultiplets, J=8.79 Hz); 7.29 (2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1605, 1590,1510, 1490, 1470, 1370, 1285, 1160.

Mass Spectrum (m/z): 358 (M⁺, ³⁵ Cl), 313, 302.

PREPARATION 34

(Z)-3-(4-Chlorophenyl)-3-(4-isobutoxyphenyl)acrylic acid

Prepared as crystals, melting at 172°-174° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 80%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.02 (6H,doublet, J=6.83 Hz); 1.95-2.20 (1H, multiplet); 3.72 (2H, doublet,J=6.84 Hz); 6.27 (1H, singlet); 6.83 (2H, doublet of multiplets, J=8.30Hz) 7.13 (2H, doublet of multiplets, J=8.30 Hz); 7.18 (2H, doublet ofmultiplets, J=8.79 Hz); 7.34 (2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1600, 1590, 1510, 1295, 1250, 1175.

Mass Spectrum (m/z): 330 (M⁺, ³⁵ Cl), 274, 257.

PREPARATION 35

(E)-3-(4-Chlorophenyl)-3-(4-isobutoxyphenyl)acrylic acid

Prepared as crystals, melting at 150°-152° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 100%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.04 (6H,doublet, J=6.35 Hz); 2.00-2.20 (1H, multiplet); 3.75 (2H, doublet,J=6.34 Hz); 6.19 (1H, singlet); 6.87 (2H, doublet of multiplets, J=8.79Hz); 7.12 (2H, doublet of multiplets, J=8.79 Hz); 7.21 (2H, doublet ofmultiplets, J=8.78 Hz); 7.30 (2H, doublet of multiplets, J=8.78 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1610, 1590, 1515, 1290, 1245, 1175.

Mass Spectrum (m/z): 330 (M⁺, ³⁵ Cl), 274, 257.

PREPARATION 36

Ethyl (Z)-3-(4-Chlorophenyl)-3-(4-propoxyphenyl)acrylate

Prepared as an oil in a yield of 19%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.03 (3H,triplet, J=7.32 Hz); 1.14 (3H, triplet, J=7.33 Hz); 1.74-1.90 (2H,multiplet); 3.92 (2H, triplet, J=6.83 Hz); 4.05 (2H, quarter, J=7.33Hz); 6.31 (1H, singlet); 6.83 (2H, doublet of multiplets, J=9.28 Hz);7.14 (1H, doublet of multiplets, J=8.79 Hz); 7.20 (2H, doublet ofmultiplets, J=9.28 Hz); 7.36 (2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1705, 1600, 1595,1510, 1370, 1275, 1250, 1160, 1150.

Mass spectrum (m/z): 344 (M⁺, ³⁵ Cl), 302, 299, 272, 257, 230.

PREPARATION 37

Ethyl (E)-3-(4-Chlorophenyl)-3-(4-propoxyphenyl)acrylate

Prepared as an oil in a yield of 27%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.05 (3H,triplet, J=7.33 Hz); 1.16 (3H, triplet, J=7.33 Hz); 1.75-1.95 (2H,multiplet); 3.95 (2H, triplet, J=6.84 Hz); 4.09 (2H, quartet, J=7.33Hz); 6.23 (1H, singlet); 6.89 (2H, doublet of multiplets, J=8.78 Hz)7.12 (2H, doublet of multiplets, J=8.78 Hz); 7.22 (2H, doublet ofmultiplets, J=8.79 Hz); 7.29 (2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1610, 1590,1510, 1490, 1370, 1290, 1240, 1170, 1150.

Mass Spectrum (m/z): 344 (M⁺, ³⁵ Cl), 302, 299, 272, 257, 230.

PREPARATION 38

(Z)-3-(4-Chlorophenyl)-3-(4-propoxyphenyl)acrylic acid

Prepared as crystals, melting at 159°-161° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 96%.

Nuclear Magnetic Resonance spectrum (CDCl₃, 270 MHz) δ ppm: 1.03 (3H,triplet, J=7.32 Hz); 1.70-1.90 (2H, multiplet); 3.93 (2H, triplet,J=6.84 Hz); 6.27 (1H, singlet); 6.83 (2H, doublet of multiplets, J=8.79Hz); 7.14 (2H, doublet of multiplets, J=8.30 Hz); 7.19 (2H, doublet ofmultiplets, J=8.79 Hz) 7.34 (2H, doublet of multiplets, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1600, 1595, 1510, 1280, 1255, 1180.

Mass Spectrum (m/z): 316 (M⁺, ³⁵ Cl), 274, 257, 229.

PREPARATION 39

(E)-3-(4-Chlorophenyl)-3-(4-propoxyphenyl)acrylic acid

Prepared as crystals, melting at 145°-147° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 97%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.06 (3H,triplet, J=7.33 Hz); 1.75-1.90 (2H, multiplet); 3.95 (3H, triplet,J=6.35 Hz); 6.19 (1H, singlet); 6.88 (2H, doublet of multiplets, J=8.79Hz); 7.13 (2H, doublet of multiplets, J=8.79 Hz); 7.21 (2H, doublet ofmultiplets, J=8.79 Hz) 7.30 (2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1610, 1590, 1510, 1495, 1290, 1270, 1250, 1175.

Mass Spectrum (m/z): 316 (M⁺, ³⁵ Cl), 274, 257, 229.

PREPARATION 40

Ethyl (E)-3-(4-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl) acrylate

Prepared as crystals, melting at 133°-135° C. (after recrystallisationfrom diethyl ether), in a yield of 22%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.15 (3H,triplet, J=7.32 Hz); 3.78 (6H, singlet); 3.87 (3H, singlet); 4.07 (2H,quartet, J=7.32 Hz); 6.31 (1H, singlet); 6.48 (2H, singlet); 7.03-7.13(2H, multiplet); 7.17-7.25 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1605, 1580,1505, 1465, 1415, 1355, 1165, 1155, 1130.

Mass Spectrum (m/z): 360 (M⁺), 345, 315.

PREPARATION 41

Ethyl (Z)-3-(4-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl) acrylate

Prepared as crystals, melting at 62°-64° C. (after recrystallisationfrom a mixture of diethyl ether and hexane), in a yield of 37%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.14 (3H,triplet, J=7.33 Hz); 3.80 (6H, singlet); 3.90 (3H, singlet); 4.08 (2H,quartet, J=7.33 Hz); 6.26 (1H, singlet); 6.41 (2H, singlet); 6.98-7.08(2H, multiplet); 7.27-7.36 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1720, 1600, 1585,1505, 1465, 1415, 1370, 1310, 1160, 1130.

Mass Spectrum (m/z): 360 (M⁺), 345, 315.

PREPARATION 42

(E)-3-(4-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl)acrylic acid

Prepared as crystals, melting at 201°-204° C. (after recrystallisationfrom a mixture of methylene chloride, diethyl ether and hexane), in ayield of 98%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.78 (6H,singlet); 3.87 (3H, singlet); 6.28 (1H, singlet); 6.46 (2H, singlet);7.02-7.12 (2H, multiplet); 7.12-7.25 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1600, 1580. 1505, 1130.

Mass Spectrum (m/z): 332 (M⁺), 317.

PREPARATION 43

(Z)-3-(4-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl)acrylic acid

Prepared as crystals, melting at 187°-189° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 100%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.79 (6H,singlet); 3.91 (3H, singlet); 6.24 (1H, singlet); 6.42 (2H, singlet);6.99-7.09 (2H, multiplet); 7.27-7.35 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1600, 1585, 1505, 1415, 1125.

Mass Spectrum (m/z): 332 (M⁺), 317.

PREPARATION 44

Ethyl (E)-3-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil in a yield of 20%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.16 (3H,triplet J=7.32 Hz); 3.83 (3H, singlet); 3.85 (3H, singlet); 3.89 (3H,singlet); 4.08 (2H, quartet, J=7.32 Hz); 6.23 (1H, singlet); 6.77-6.89(3H, multiplet); 6.91 (2H, doublet of multiplets, J=8.78 Hz); 7.16 (2H,doublet of multiplets, J=8.78 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1705, 1605, 1580,1510, 1465, 1290, 1165, 1135.

Mass Spectrum (m/z): 342 (M⁺), 313, 297.

PREPARATION 45

Ethyl (Z)-3-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil in a yield of 30%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.15 (3H,triplet J=7.32 Hz); 3.81 (3H, singlet); 3.85 (3H, singlet); 3.92 (3H,singlet); 4.07 (2H, quartet, J=7.32 Hz); 6.24 (1H, singlet); 6.71 (1H,doublet, J=1.95 Hz); 6.77-6.94 (4H, multiplet); 7.26 (2H, doublet ofmultiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1705, 1600, 1510,1465, 1250, 1170, 1135.

Mass Spectrum (m/z): 342 (M⁺), 313, 297.

PREPARATION 46

(E)-3-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 161°-163° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 91%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.82 (3H,singlet); 3.85 (3H, singlet); 3.89 (3H, singlet); 6.20 (1H, singlet);6.74-6.82 (2H, multiplet); 6.84 (1H, broad singlet); 6.89 (2H, doubletof multiplets, J=8.79 Hz); 7.17 (2H, doublet of multiplets, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1685, 1605, 1595, 1510, 1465, 1290, 1245, 1170, 1135.

Mass Spectrum (m/z): 314 (M⁺), 299.

PREPARATION 47

(Z)-3-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 149°-152° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 97%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.81 (3H,singlet); 3.83 (3H, singlet); 3.92 (3H, singlet); 6.21 (1H, singlet);6.74 (1H, doublet, J=1.95 Hz); 6.80 (1H, doublet of doublets, J=8.30 &1.95 Hz); 6.82-6.93 (3H, multiplet); 7.14-7.29 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1600, 1515, 1465, 1255, 1175, 1135.

Mass Spectrum (m/z): 314 (M⁺), 299, 270.

PREPARATION 48

Ethyl (Z)-3-(3,4-Dichlorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil in a yield of 62%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 1.15 (3H,triplet, J=7 Hz); 3.80 (3H, singlet); 4.06 (2H, quartet J=7 Hz); 6.35(1H, singlet); 6.8-7.4 (7H, multiplet).

PREPARATION 49

Ethyl (E)-3-(3,4-Dichlorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil in a yield of 23%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 1.16 (3H,triplet, J=7 Hz); 3.84 (3H, singlet); 4.06 (2H, quartet J=7 Hz); 6.23(1H, singlet); 6.7-7.5 (7H, multiplet).

PREPARATION 50

(Z)-3-(3,4-Dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 181°-184° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 84%.

Nuclear Magnetic Resonance Spectrum (CD₃ OD, 270 MHz) δ ppm: 3.80 (3H,singlet); 6.36 (1H, singlet); 6.91 (2H, doublet of multiplets, J=9.28Hz); 7.08 (1H, doublet of doublets, J=8.30 & 1.95 Hz); 7.23 (2H, doubletof multiplets, J=9.28 Hz); 7.31 (1H, doublet, J=1.95 Hz); 7.51 (1H,doublet, J=8.30 Hz).

Infrared Absorption Spectrum (KBr) ν_(max) cm⁻¹ : 2300-3400 (broad),1692, 1597, 1585, 1510, 1288, 1254, 1214, 1178, 1162.

Mass Spectrum (m/z): 322 (M⁺, ³⁵ Cl), 305, 277.

PREPARATION 51

(E)-3-(3,4-Dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 193°-196° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 95%.

Nuclear Magnetic Resonance Spectrum (CD₃ OD, 270 MHz) δ ppm: 3.83 (3H,singlet); 6.30 (1H, singlet); 6.93 (2H, doublet of multiplets, J=8.79Hz); 7.12 (2H, doublet of multiplets, J=8.79 Hz); 7.23 (1H, doublet ofdoublets, J=8.30 & 1.95 Hz); 7.38 (1H, doublet, J=1.95 Hz); 7.50 (1H,doublet, J=8.30 Hz).

Infrared Absorption Spectrum (KBr) ν_(max) cm⁻¹ : 2300-3400 (broad),1688, 1662, 1602, 1512, 1407, 1281, 1253, 1207, 1177.

Mass Spectrum (m/z): 322 (M⁺, ³⁵ Cl), 305, 277.

PREPARATION 52

Ethyl (E)-3-(3,4-Dimethoxyphenyl)-3-(3-trifluoromethylphenyl)acrylate

Prepared as crystals, melting at 72°-74° C. (after recrystallisationfrom hexane), in a yield of 13%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.08 (3H,triplet, J=7.32 Hz); 3.84 (3H, singlet); 3.89 (3H, singlet); 4.03 (2H,quartet, J=7.32 Hz); 6.37 (1H, singlet); 6.72 (1H, doublet of doublets,J=8.30 & 1.96 Hz); 6.80 (1H, doublet, J=8.30 Hz); 6.87 (1H, doublet,J=1.96 Hz); 7.35-7.70 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1595, 1515,1460, 1370.

Mass Spectrum (m/z): 380(M⁺), 361, 335.

PREPARATION 53

Ethyl (Z)-3-(3,4-Dimethoxyphenyl)-3-(3-trifluoromethylphenyl)acrylate

Prepared as an oil in a yield of 16%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.18 (3H,triplet, J=7.32 Hz); 3.82 (3H, singlet); 3.93 (3H, singlet); 4.11 (2H,quartet, J=7.32 Hz); 6.30 (1H, singlet): 6.71 (1H, doublet, J=1.95 Hz);6.81 (1H, doublet of doublets, J=8.30 & 1.96 Hz); 6.89 (1H, doublet,J=8.30 Hz); 7.40-7.50 (2H, multiplet); 7.57-7.68 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1600, 1580,1515, 1460, 1370, 1325.

Mass Spectrum (m/z): 380(M⁺), 361, 335.

PREPARATION 54

(E)-3-(3,4-Dimethoxyphenyl)-3-(3-trifluoromethylphenyl)acrylic acid

Prepared as crystals (melting at 142°-144° C., after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 100%.

PREPARATION 55

(Z)-3-(3,4-Dimethoxyphenyl)-3-(3-trifluoromethylphenyl)acrylic acid

Prepared as crystals (melting at 140°-143° C., after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 100%.

PREPARATION 56

Ethyl (E)-3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylate

Prepared as crystals, melting at 75°-77° C. (after recrystallisationfrom hexane), in a yield of 21%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.14 (3H,triplet, J=7.32 Hz); 2.39 (3H, singlet); 3.83 (3H, singlet); 3.88 (3H,singlet); 4.06 (2H, quartet, J=7.32 Hz); 6.27 (1H, singlet): 6.77 (1H,doublet, J=8.30 Hz); 6.81 (1H, doublet of doublets, J=8.30 & 1.95 Hz);6.89 (1H, doublet, J=1.95 Hz); 7.01-7.22 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1705, 1600, 1580,1510, 1465, 1440, 1370, 1290, 1250, 1160, 1130.

Mass Spectrum (m/z): 326 (M⁺), 297, 281, 254.

PREPARATION 57

Ethyl (Z)-3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylate

Prepared as crystals (melting at 69°-70° C. after recrystallisation fromhexane), in a yield of 38%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.16 (3H,triplet, J=7.32 Hz); 2.36 (3H, singlet); 3.81 (3H, singlet); 3.91 (3H,singlet); 4.08 (2H, quartet, J=7.32 Hz); 6.27 (1H, singlet): 6.72 (1H,doublet, J=1.95 Hz); 6.81 (1H, doublet of doublets, J=7.81 & 1.95 Hz);6.88 (1H, doublet, J=7.81 Hz). 7.13 (2H, doublet of multiplets, J=8.30Hz); 7.21 (2H, doublet of multiplets, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1600, 1580,1510, 1465, 1415, 1370, 1250, 1160, 1135.

Mass Spectrum (m/z): 326 (M⁺), 297, 281, 254.

PREPARATION 58

(E)-3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylic acid

Prepared as crystals, melting at 167°-170° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 97%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.39 (3H,singlet); 3.88 (3H, singlet); 3.92 (3H, singlet); 6.24 (1H, singlet);7.79 (1H, multiplet); 6.86 (1H, broad singlet); 7.08-7.22 (4H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1600, 1580, 1510, 1465, 1440, 1420, 1325, 1290, 1250, 1175, 1135.

Mass Spectrum (m/z): 298(M⁺), 283.

PREPARATION 59

(Z)-3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylic acid

Prepared as crystals, melting at 185°-188° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 96%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.36 (3H,singlet); 3.80 (3H, singlet); 3.92 (3H, singlet); 6.24 (1H, singlet);6.75 (1H, doublet, J=1.95 Hz); 6.79 (1H, doublet of doublets, J=8.30 &1.95 Hz); 6.86 (1H, doublet, J=8.30 Hz); 7.10-7.23 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1605, 1515, 1465, 1420, 1260, 1180, 1140.

Mass Spectrum (m/z): 298 (M⁺), 283.

PREPARATION 60

Ethyl (Z)-3-(3,4-Dichlorophenyl)-3-(3-methylphenyl)acrylate

Prepared as an oil in a yield of 52%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.17 (3H,triplet, J=7.32 Hz); 2.33 (3H, singlet); 4.08 (2H, quartet, J=7.32 Hz);6.36 (1H, singlet); 7.03-7.13 (3H, multiplet); 7.15-7.23 (2H,multiplet); 7.30 (1H, doublet, J=1.95 Hz); 7.46 (1H, doublet, J=8.30Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1715, 1620, 1470,1370, 1280, 1170, 1150.

Mass Spectrum (m/z): 334 (M⁺, ³⁵ Cl), 305, 289, 262.

PREPARATION 61

Ethyl (E)-3-(3,4-Dichlorophenyl)-3-(3-methylphenyl)acrylate

Prepared as an oil in a yield of 19%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.11 (3H,triplet, J=7.32 Hz); 2.35 (3H, singlet); 4.05 (2H, quartet, J=7.32 Hz);6.30 (1H, singlet); 6.95-7.05 (2H, multiplet); 7.12 (1H, doublet ofdoublets, J=8.79 & 1.95 Hz); 7.15-7.32 (2H, multiplet); 7.379 (1H,doublet, J=1.95 Hz); 7.385 (1H, doublet, J=8.79 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1720, 1620, 1470,1380, 1370, 1350, 1280, 1250, 1175.

Mass Spectrum (m/z): 334 (M⁺, ³⁵ Cl), 305, 289, 262.

PREPARATION 62

(Z)-3-(3,4-Dichlorophenyl)-3-(3-methylphenyl)acrylic acid

Prepared as crystals, melting at 163°-165° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 95%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.33 (3H,singlet); 6.33 (1H, singlet); 7.00-7.10 (3H, multiplet); 7.18-7.28 (2H,multiplet); 7.29 (1H, doublet, J=1.95 Hz); 7.45 (1H, doublet, J=7.81Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1600, 1585, 1475, 1290, 1125.

Mass Spectrum (m/z): 306 (M⁺, ³⁵ Cl), 291, 261.

PREPARATION 63

(E)-3-(3,4-Dichlorophenyl)-3-(3-methylphenyl)acrylic acid

Prepared as crystals, melting at 152°-154° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 92%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.34 (3H,singlet); 6.26 (1H, singlet); 6.94-7.03 (2H, multiplet); 7.09 (1H,doublet of doublets, J=8.30 & 1.95 Hz); 7.18-7.32 (2H, multiplet); 7.35(1H, doublet, J=1.96 Hz); 7.39 (1H, doublet, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1620, 1470, 1410, 1285, 1180, 1130.

Mass Spectrum (m/z): 306 (M⁺, ³⁵ Cl), 291, 261.

PREPARATION 64

Ethyl (E)-3-(3,4-Dimethoxyphenyl)-3-(3-methylphenyl)acrylate

Prepared as an oil in a yield of 23%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.11 (3H,triplet, J=7.32 Hz); 2.36 (3H, singlet); 3.83 (3H, singlet); 3.88 (3H,singlet); 4.04 (2H, quartet, J=7.32 Hz); 6.29 (1H, singlet); 6.75-6.84(2H, multiplet); 6.90 (1H, broad singlet); 6.94-7.05 (2H, multiplet);7.15-7.31 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1600, 1580,1515, 1470, 1445, 1330, 1295, 1255, 1160, 1145, 1130.

Mass Spectrum (m/z): 326 (M⁺), 297, 281, 254.

PREPARATION 65

Ethyl (Z)-3-(3,4-Dimethoxyphenyl)-3-(3-methylphenyl)acrylate

Prepared as an oil in a yield of 33%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.16 (3H,triplet, J=7.33 Hz); 2.33 (3H, singlet); 3.81 (3H, singlet); 3.92 (3H,singlet); 4.08 (2H, quartet, J=7.32 Hz); 6.72 (1H, doublet, J=1.96 Hz);6.81 (1H, doublet of doublets, J=8.30 & 1.96 Hz); 6.88 (1H, doublet,J=8.30 Hz); 7.07-7.26 (4H, multiplet.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1715, 1610, 1590,1520, 1470, 1260, 1180, 1160, 1145, 1135.

Mass Spectrum (m/z): 326 (M⁺), 297, 281, 254.

PREPARATION 66

(E)-3-(3,4-Dimethoxyphenyl)-3-(3-methylphenyl)acrylic acid

Prepared as crystals, melting at 140°-143° C. (after recrystallisationfrom a mixture of diethyl ether and hexane), in a yield of 95%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.35 (3H,singlet); 3.82 (3H, singlet); 3.89 (3H, singlet); 6.27 (1H, singlet);6.74-6.83 (2H, multiplet); 6.87 (1H, broad singlet); 6.99-7.06 (2H,multiplet); 7.15-7.31 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1600, 1580, 1515, 1470, 1260, 1170, 1145, 1130.

Mass Spectrum (m/z): 298 (M⁺), 283, 253.

PREPARATION 67

(Z)-3-(3,4-Dimethoxyphenyl)-3-(3-methylphenyl)acrylic acid

Prepared as crystals, melting at 148°-150° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 96%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.33 (3H,singlet); 3.81 (3H, singlet); 3.92 (3H, singlet); 6.24 (2H, singlet);6.75 (1H, doublet, J=1.96 Hz); 6.80 (1H, doublet of doublets, J=8.30 &1.96 Hz); 6.87 (1H, doublet, J=8.30 Hz); 7.05-7.14 (2H, multiplet);7.16-7.24 (2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1605, 1585, 1515, 1450, 1440, 1420, 1255, 1175, 1135.

Mass Spectrum (m/z): 298 (M⁺), 283, 253.

PREPARATION 68

Ethyl (Z)-3-(2-Chlorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil in a yield of 81%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.10 (3H,triplet, J=7.33 Hz); 3.81 (3H, singlet); 4.03 (2H, quartet, J=7.33 Hz);6.48 (1H, singlet); 6.85 (2H, doublet of multiplets, J=9.28 Hz);7.11-7.20 (1H, multiplet); 7.26 (2H, doublet of multiplets, J=9.28 Hz);7.26-7.37 (2H, multiplet); 7.40-7.50 (1H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1605, 1590,1575, 1515, 1465, 1370, 1355, 1280, 1255, 1160.

Mass Spectrum (m/z): 316 (M⁺, ³⁵ Cl), 281, 271, 253.

PREPARATION 69

(Z)-3-(2-Chlorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 162°-164° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 85%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.80 (3H,singlet); 6.44 (1H, singlet); 6.84 (2H, doublet of multiplets, J=8.79Hz); 7.09-7.16 (1H, multiplet); 7.24 (2H, doublet of multiplets, J=8.79Hz); 7.24 (2H, doublet of multiplets, J=8.79 Hz); 7.26-7.35 (2H,multiplet); 7.37-7.46 (1H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1700, 1620, 1605, 1595, 1575, 1515, 1425, 1290, 1260, 1180, 1160.

Mass Spectrum (m/z): 288 (M⁺, ³⁵ Cl), 253, 238.

PREPARATION 70

Ethyl (Z)-3-(3-Chlorophenyl)-3-(3-methoxyphenyl)acrylate

Prepared as an oil in a yield of 8%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.13 (3H,triplet, J=7.32 Hz); 3.78 (3H, singlet); 4.06 (2H, quartet, J=7.32 Hz);6.37 (1H, singlet); 6.81 (1H, triplet, J=1.96 Hz); 6.86 (1H, doubleddoublet of doublets, J=8.31, 1.96 & 0.98 Hz); 6.91 (1H, doubled doubletof doublets, J=8.31, 1.96 & 0.98 Hz); 7.10 (1H, doublet of triplets,J=7.81 & 1.95 Hz); 7.20 (1H, triplet, J=1.95 Hz); 7.25 (1H, triplet,J=7.81 Hz); 7.31 (1H, triplet, J=7.81 Hz); 7.35 (1H, doublet oftriplets, J=7.81 & 1.95 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1715, 1620, 1600,1580, 1490, 1470, 1435, 1370, 1350, 1290, 1280, 1170.

Mass Spectrum (m/z): 316 (M⁺, ³⁵ Cl), 287, 271, 243, 228.

PREPARATION 71

Ethyl (E)-3-(3-Chlorophenyl)-3-(3-methoxyphenyl)acrylate

Prepared as an oil in a yield of 18%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.12 (3H,triplet, J=7.32 Hz); 3.79 (3H, singlet); 4.06 (2H, quartet, J=7.32 Hz);6.33 (1H, singlet); 6.72 (1H, doublet of doublets, J=2.44 & 1.46 Hz);6.79 (1H, doublet of triplets, J=7.81 & 1.46 Hz); 6.93 (1H, doubleddoublet of doublets, J=8.30, 2.44 & 1.46 Hz); 7.18 (1H, doublet oftriplets, J=7.32 & 1.46 Hz); 7.22-7.36 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1720, 1620, 1590,1580, 1570, 1490, 1470, 1430, 1370, 1350, 1290, 1260, 1170.

Mass Spectrum (m/z): 316 (M⁺, ³⁵ Cl), 287, 271, 243, 228.

PREPARATION 72

(Z)-3-(3-Chlorophenyl)-3-(3-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 115°-117° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 98%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.78 (3H,singlet); 6.35 (1H, singlet); 6.78 (1H, triplet, J=1.47 Hz); 6.84 (1H,doublet of multiplets, J=7.81 Hz); 6.93 (1H, doublet of multiplets,J=7.81 Hz); 7.10 (1H, doublet of triplets, J=7.32 & 1.47 Hz); 7.25 (1H,triplet, J=7.81 Hz); 7.30 (1H, triplet, J=7.32 Hz); 7.36 (1H, doublet oftriplets, J=7.33 & 1.47 Hz);

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1620, 1600, 1580, 1490, 1435, 1410, 1345, 1290, 1150.

Mass Spectrum (m/z): 288 (M⁺, ³⁵ Cl), 271, 243.

PREPARATION 73

(E)-3-(3-Chlorophenyl)-3-(3-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 140°-142° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 96%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.79 (3H,singlet); 6.30 (1H, singlet); 6.72 (1H, doublet of doublets, J=2.44 &1.47 Hz); 6.78 (1H, doublet of multiplets, J=7.32 Hz); 6.93 (1H, doubleddoublet of doublets, J=8.30, 2.44 & 0.97 Hz); 7.16 (1H, doublet oftriplets, J=7.81 & 1.47 Hz); 7.23-7.38 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1620, 1600, 1590, 1570, 1490, 1470, 1460, 1430, 1350, 1285.

Mass Spectrum (m/z): 288 (M⁺, ³⁵ Cl), 271, 243.

PREPARATION 74

Ethyl (Z)-3-(3-Chlorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil in a yield of 10%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.12 (3H,triplet, J=7.32 Hz); 3.82 (3H, singlet); 4.05 (2H, quartet, J=7.32 Hz);6.32 (1H, singlet); 6.85 (2H, doublet of multiplets, J=9.28 Hz); 7.09(1H, doublet of triplets, J=7.30 & 1.96 Hz); 7.18-7.39 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm³¹ 1 : 1710, 1605, 1600,1570, 1515, 1465, 1420, 1370, 1350, 1290, 1275, 1255, 1170, 1155.

Mass Spectrum (m/z): 316 (M⁺, ³⁵ Cl), 287, 271, 244, 228.

PREPARATION 75

Ethyl (E)-3-(3-Chlorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil in a yield of 14%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.17 (3H,triplet, J=7.32 Hz); 3.84 (3H, singlet); 4.09 (2H, quartet, J=7.32 Hz);6.25 (1H, singlet); 6.91 (2H, doublet of multiplets, J=8.79 Hz); 7.14(2H, doublet of multiplets, J=8.79 Hz); 7.15-7.36 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1715, 1610, 1570,1515, 1470, 1370, 1355, 1295, 1250, 1175.

Mass Spectrum (m/z): 316 (M⁺, .sup.± Cl), 287, 271, 244, 288.

PREPARATION 76

(Z)-3-3-Chlorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 158°-160° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 94%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.82 (3H,singlet); 6.29 (1H, singlet); 6.85 (2H, doublet of multiplets, J=9.28Hz); 7.09 (2H, doublet of triplets, J=7.30 & 1.46 Hz); 7.16-7.38 (5H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1605, 1590, 1570, 1515, 1425, 1285, 1255, 1180.

Mass Spectrum (m/z): 288 (M⁺, ³⁵ Cl), 271, 243.

PREPARATION 77

(E)-3-(3-Chlorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 119°-120° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 92%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.85 (3H,singlet); 6.21 (1H, singlet); 6.90 (2H, doublet of multiplets, J=8.79Hz); 7.15 (2H, doublet of multiplets, J=8.79 Hz); 7.12-7.38 (4H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1610, 1570, 1515, 1420, 1295, 1250, 1180.

Mass Spectrum (m/z): 288 (M⁺, ³⁵ Cl), 271, 243.

PREPARATION 78

Ethyl (Z)-3-(3,4-Dichlorophenyl)-3-(4-propoxyphenyl)acrylate

Prepared as an oil, in a yield of 4%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.03 (3H,triplet, J=7.32 Hz); 1.16 (3H, triplet, J=7.32 Hz); 1.70-1.90 (2H,multiplet); 3.93 (2H, triplet, J=6.84 Hz); 4.07 (2H, quartet, J=7.32Hz); 6.32 (1H, singlet); 6.84 (2H, doublet of multiplets, J=8.79 Hz);7.06 (1H, doublet of doublets, J=8.30 & 1.95 Hz); 7.20 (2H, doublet ofmultiplets, J=8.79 Hz); 7.29 (1H, doublet, J=1.95 Hz); 7.45 (1H,doublet, J=8.30 Hz).

Mass Spectrum (m/z): 378 (M⁺, ³⁵ Cl), 336, 333, 308, 305, 291, 264.

PREPARATION 79

Ethyl (E)-3-(3,4-Dichlorophenyl)-3-(4-propoxyphenyl)acrylate

Prepared as an oil, in a yield of 5%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.05 (3H,triplet, J=7.32 Hz); 1.17 (3H, triplet, J=7.32 Hz); 1.75-1.90 (2H,multiplet); 3.95 (2H, triplet, J=6.35 Hz); 4.09 (2H, quartet, J=7.32Hz); 6.22 (1H, singlet); 6.90 (2H, doublet of multiplets, J=8.79 Hz);7.11 (2H, doublet of multiplets, J=8.79 Hz): 7.13 (1H, doublet ofdoublets, J=8.30 & 1.96 Hz); 7.38 (1H, doublet, J=1.96 Hz); 7.39 (1H,doublet, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1715, 1630, 1515,1470, 1390, 1370, 1350, 1290, 1280, 1245, 1170.

Mass Spectrum (m/z): 378 (M⁺, ³⁵ Cl), 336, 333, 308, 305, 291, 264.

PREPARATION 80

(Z)-3-(3,4-Dichlorophenyl)-3-(4-propoxyphenyl)acrylic acid

Prepared as crystals, melting at 161°-163° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 96%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.03 (3H,triplet, J=7.32 Hz); 1.70-1.90 (2H, multiplet); 3.93 (2H, triplet,J=6.84 Hz); 6.29 (1H, singlet); 6.85 (2H, doublet of multiplets, J=8.79Hz); 7.06 (1H, doublet of doublets, J=8.30 & 1.95 Hz); 7.19 (2H, doubletof multiplets, J=8.79 Hz); 7.28 (1H, doublet, J=1.95 Hz); 7.45 (1H,doublet, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1605, 1590, 1515, 1475, 1285, 1255, 1180.

Mass Spectrum (m/z): 350 (M⁺, ³⁵ Cl), 308, 291, 263.

PREPARATION 81

(E)-3-(3,4-Dichlorophenyl)-3-(4-propoxyphenyl)acrylic acid

Prepared as crystals, melting at 155°-157° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 85%.

PREPARATION 82

Ethyl (E)-3-(4-ethoxy-3-methoxyphenyl)cinnamate

Prepared as crystals, melting at 89°-91° C. (after recrystallizationfrom hexane), in a yield of 21%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.10 (3H,triplet, J=7.32 Hz); 1.46 (3H, triplet, J=7.33 Hz); 3.81 (3H, singlet);4.03 (2H, quartet, J=7.33 Hz); 4.10 (2H, quartet, J=7.33 Hz); 6.31 (1H,singlet); 6.77 (2H, broad singlet); 6.90 (1H, broad singlet); 7.16-7.25(2H, multiplet); 7.32-7.41 (3H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1615, 1600,1580, 1515, 1480, 1470, 1370, 1320, 1290, 1250, 1160, 1135.

Mass Spectrum (m/z): 326 (M⁺), 297, 281, 253, 226.

PREPARATION 83

Ethyl (Z)-3-(4-ethoxy-3-methoxyphenyl)cinnamate

Prepared as an oil, in a yield of 21%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.15 (3H,triplet, J=7.32 Hz); 1.49 (3H, triplet, J=7.32 Hz); 3.80 (3H, singlet);4.08 (2H, quartet, J=7.32 Hz); 4.14 (2H, quartet, J=7.32 Hz); 6.28 (1H,singlet); 6.73 (1H, doublet, J=1.95 Hz); 6.79 (1H, doublet of doublets,J=8.30 & 1.95 Hz); 6.87 (1H, doublet, J=8.30 Hz); 7.29-7.40 (5H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1605, 1580,1515, 1480, 1470, 1450, 1410, 1370, 1355, 1320, 1250, 1160, 1130.

Mass Spectrum (m/z): 326 (M⁺), 297, 281, 253, 226.

PREPARATION 84

(E)-3-(4-Ethoxy-3-methoxyphenyl)cinnamic acid

Prepared as crystals, melting at 200°-202° C. (after recrystallizationfrom a mixture of tetrahydrofuran and hexane), in a yield of 93%.

Nuclear Magnetic Resonance Spectrum (a 1:1 by volume mixture of CDCl₃and CD₃ OD, 270 MHz) δ ppm: 1.45 (3H, triplet, J=6.96 Hz); 3.80 (3H,singlet); 4.11 (2H, quartet, J=6.96 Hz); 6.32 (1H, singlet); 6.80 (1H,doublet of doublets, J=8.43 & 1.83 Hz); 6.84 (1H, doublet, J=8.43 Hz);6.88 (1H, doublet, J=1.83 Hz); 7.18-7.27 (2H, multiplet); 7.32-7.42 (3H,multiplet).

Infrared Absorption Spectrum (KBr) ν_(max) cm⁻¹ : 2400-3600 (broad),1692, 1660, 1605, 1587, 1514, 1479, 1421, 1402, 1324, 1297, 1274, 1255,1204, 1137.

Mass Spectrum (m/z): 298 (M⁺), 270, 253, 225.

PREPARATION 85

(Z)-3-(4-Ethoxy-3-methoxyphenyl)cinnamic acid

Prepared as crystals, melting at 133°-135° C. (after recrystallizationfrom a mixture of methylene chloride and hexane), in a yield of 90%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.49 (3H,triplet, J=7.32 Hz); 3.80 (3H, singlet); 4.14 (2H, quartet, J=7.32 Hz);6.25 (1H, singlet); 6.72-6.86 (3H, multiplet); 7.27-7.43 (5H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1605, 1580, 1515, 1470, 1450, 1415, 1255, 1135.

Mass Spectrum (m/z): 298 (M⁺), 270, 253, 225.

PREPARATION 86

Ethyl (E)-3-(4-butoxy-3-methoxyphenyl)cinnamate

Prepared as an oil, in a yield of 21%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.43-1.54(2H, multiplet); 1.78-1.86 (2H, multiplet); 3.80 (3H, singlet); 4.02(2H, triplet, J=6.84 Hz); 4.03 (2H, quartet, J=7.33 Hz); 6.31 (1H,singlet); 6.77 (1H, broad singlet); 6.79 (2H, broad singlet); 7.17-7.24(2H, multiplet); 7.34-7.41 (3H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1690, 1610,1595, 1580, 1510, 1465, 1370, 1290, 1270, 1250, 1160, 1135.

Mass Spectrum (m/z): 354 (M⁺), 309, 298, 269, 253, 226.

PREPARATION 87

Ethyl (Z)-3-(4-butoxy-3-methoxyphenyl)cinnamate

Prepared as an oil, in a yield of 47%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 0.98 (3H,triplet, J=7 Hz); 1.13 (3H, triplet, J=7 Hz); 1.30-2.20 (4H, multiplet);3.78 (3H, singlet); 4.02 (2H, triplet, J=7 Hz); 4.10 (2H, quartet, J=7Hz); 6.30 (1H, singlet); 6.70-7.05 (3H, multiplet).

PREPARATION 88

(E)-3-(4-Butoxy-3-methoxyphenyl)cinnamate

Prepared as crystals, melting at 140°-143° C. (after recrystallizationfrom a mixture of methylene chloride and hexane), in a yield of 92%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 0.97 (3H,triplet, J=7.33 Hz); 1.40-1.60 (2H, multiplet); 1.75-1.90 (2H,multiplet); 3.79 (3H, singlet); 4.02 (2H, triplet, J=6.84 Hz); 6.28 (1H,singlet); 6.75 (1H, doublet of doublets, J=8.78 & 1.47 Hz); 6.78 (1H,doublet, J=8.78 Hz); 6.85 (1H, doublet, J=1.47 Hz); 7.17-7.24 (2H,multiplet); 7.30-7.40 (3H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1610, 1595, 1580, 1510, 1500, 1470, 1420, 1320, 1250, 1135.

Mass Spectrum (m/z): 326 (M⁺), 270, 253, 237.

PREPARATION 89

Ethyl (Z)-3-(3,4-dichlorophenyl)-3-(4-ethylphenyl)acrylate

Prepared as an oil, in a yield of 50%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.16 (3H,triplet, J=7.32 Hz); 1.24 (3H, triplet, J=7.32 Hz); 2.66 (2H, quartet,J=7.32 Hz); 4.08 (2H, quartet, J=7.32 Hz); 6.37 (1H, singlet); 7.06 (1H,doublet of doublets, J=8.30 & 1.95 Hz); 7.12-7.24 (4H, multiplet); 7.30(1H, doublet, J=1.95 Hz); 7.46 (1H, doublet, J=8.30 Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1620, 1610,1470, 1370, 1275, 1170, 1160.

Mass Spectrum (m/z): 348 (M⁺, ³⁵ Cl), 319, 303, 276.

PREPARATION 90

Ethyl (E)-3-(3,4-dichlorophenyl)-3-(4-ethylphenyl)-acrylate

Prepared as an oil, in a yield of 14%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 1.10 (3H,triplet, J=7 Hz); 1.27 (3H, triplet, J=7 Hz); 2.70 (2H, quartet, J=7Hz); 4.05 (2H, quartet, J=7 Hz); 6.27 (1H, singlet); 6.98-7.60 (7H,multiplet).

PREPARATION 91

(Z)-3-(3,4-Dichlorophenyl)-3-(4-ethylphenyl)acrylic acid

Prepared as crystals, melting at 172°-174° C. (after recrystallizationfrom a mixture of methylene chloride and hexane), in a yield of 94%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.24 (3H,triplet, J=7.32 Hz); 2.66 (2H, quartet, J=7.32 Hz); 6.35 (1H, singlet);7.06 (1H, doublet of doublets, J=7.82 & 1.95 Hz); 7.12-7.24 (4H,multiplet); 7.29 (1H, doublet, J=1.95 Hz); 7.45 (1H, doublet, J=7.82Hz).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1620, 1605, 1470, 1280, 1180, 1160, 1120.

Mass Spectrum (m/z): 320 (M⁺, ³⁵ Cl), 305, 291, 275.

PREPARATION 92

Ethyl (Z)-3-(4-propoxyphenyl)cinnamate

Prepared as an oil, in a yield of 35%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.05 (3H,triplet, J=7.33 Hz); 1.67 (3H, triplet, J=7.33 Hz); 1.75-1.90 (2H,multiplet); 3.95 (2H, triplet, J=6.60 Hz); 4.09 (2H, quartet, J=7.33Hz); 6.26 (1H, singlet); 6.89 (2H, doublet of multiplets, J=8.80 Hz);7.14 (2H, doublet of multiplets, J=8.80 Hz); 7.26-7.40 (5H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1610, 1510,1370, 1290, 1260, 1240, 1170.

Mass Spectrum (m/z): 310 (M⁺), 268, 265, 238, 223, 196.

PREPARATION 93

Ethyl (E)-3-(4-propoxyphenyl)cinnamate

Prepared as an oil, in a yield of 35%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.03 (3H,triplet, J=7.33 Hz); 1.10 (3H, triplet, J=7.33 Hz); 1.75-1.90 (2H,multiplet); 3.92 (2H, triplet, J=6.84 Hz); 4.03 (2H, quartet, J=7.33Hz); 6.30 (1H, singlet); 6.82 (2H, doublet of multiplets, J=9.27 Hz);7.15-7.28 (2H, multiplet); 7.23 (2H, doublet of multiplets, J=9.27 Hz);7.28-7.43 (3H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1605, 1595,1575, 1510, 1370, 1250, 1160, 1150.

Mass Spectrum (m/z): 310 (M⁺), 268, 265, 238, 223, 196.

PREPARATION 94

(Z)-3-(4-Propoxyphenyl)cinnamic acid

Prepared as crystals, melting at 183°-185° C. (after recrystallizationfrom a mixture of methylene chloride and hexane), in a yield of 93%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.06 (3H,triplet, J=7.33 Hz); 1.75-1.90 (2H, multiplet); 3.95 (2H, triplet,J=6.84 Hz); 6.23 (1H, singlet); 6.88 (2H, doublet of multiplets, J=8.79Hz); 7.15 (2H, doublet of multiplets, J=8.79 Hz); 7.26-7.42 (5H,multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1695, 1610, 1515, 1290, 1280, 1250, 1175.

Mass Spectrum (m/z): 282 (M⁺), 240, 223, 195.

PREPARATION 95

(E)-3-(4-Propoxyphenyl)cinnamic acid

Prepared as crystals, melting at 138°-140° C. (after recrystallizationfrom a mixture of methylene chloride and hexane), in a yield of 92%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz δ ppm: 1.00 (2H,triplet, J=7 Hz); 1.45-2.20 (2H, multiplet); 3.90 (2H, quartet, J=7 Hz);6.27 (1H, singlet); 6.83 (2H, doublet of multiplets, J=9 Hz); 7.05-7.60(7H, multiplet); 10.00 (1H, broad multiplet).

PREPARATION 96

(E)-3-(3,4-Methylenedioxyphenyl)cinnamic acid

Prepared as crystals, melting at 222°-224° C. (after recrystallizationfrom a mixture of diethyl ether and tetrahydrofuran), in a yield of 22%.

Nuclear Magnetic Resonance Spectrum (a 1:1 by volume mixture of CDCl₃and CD₃ OD, 60 MHz) δ ppm: 5.99 (2H, singlet); 6.29 (1H, singlet); 6.79(3H, singlet); 7.05-7.60 (5H, multiplet).

PREPARATION 97

(Z)-3-(3,4-Methylenedioxyphenyl)cinnamic acid

Prepared as crystals, melting at 141°-143° C. (after recrystallizationfrom a mixture of methylene chloride and hexane), in a yield of 51%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 6.00 (2H,singlet); 6.26 (1H, singlet); 6.72-6.96 (3H, multiplet); 7.15-7.55 (5H,multiplet).

PREPARATION 98

Ethyl (E)-3-(3-methoxy-4-propoxyphenyl)-3-(3-methylphenyl)acrylate

Prepared as an oil, in a yield of 22%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.03 (3H,triplet, J=7.32 Hz); 1.11 (3H, triplet, J=7.32 Hz); 1.80-1.95 (2H,multiplet); 2.35 (3H, singlet); 3.81 (3H, singlet); 3.98 (2H, triplet,J=6.84 Hz); 4.04 (2H, quartet, J=7.32 Hz); 6.29 (1H, singlet); 6.72-6.86(2H, multiplet); 6.90 (1H, broad singlet); 6.98-7.05 (2H, multiplet);7.15-7.24 (1H, multiplet); 7.30-7.42 (1H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1600, 1580,1510, 1485, 1370, 1290, 1260, 1160, 1145, 1130.

Mass Spectrum (m/z): 354 (M⁺), 312, 267, 240.

PREPARATION 99

Ethyl (Z)-3-(3-methoxy-4-propoxyphenyl)-3-(3-methylphenyl)acrylate

Prepared as an oil, in a yield of 40%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.05 (3H,triplet, J=7.32 Hz); 1.15 (3H, triplet, J=7.32 Hz); 1.80-1.95 (2H,multiplet); 2.32 (3H, singlet); 3.80 (3H, singlet); 4.02 (2H, triplet,J=6.84 Hz); 4.08 (2H, quartet, J=7.32 Hz); 6.26 (1H, singlet); 6.72 (1H,doublet, J=1.96 Hz); 6.78 (1H, doublet of doublets, J=7.82 & 1.96 Hz);6.87 (1H, doublet, J=7.82 Hz); 7.06-7.25 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1605, 1590,1515, 1465, 1370, 1250, 1180, 1160, 1130.

Mass Spectrum (m/z): 354 (M⁺), 312, 267, 240.

PREPARATION 100

(E)-3-(3-methoxy-4-propoxyphenyl)-3-(3-methylphenyl)acrylic acid

Prepared as crystals, melting at 123°-126° C. (after recrystallizationfrom a mixture of methylene chloride and hexane), in a yield of 98%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.03 (3H,triplet, J=7.33 Hz); 1.75-1.95 (2H, multiplet); 2.34 (3H, singlet); 3.80(3H, singlet); 3.98 (2H, triplet, J=6.84 Hz); 6.26 (1H, singlet); 6.74(1H, doublet of doublets, J=8.79 & 1.93 Hz); 6.78 (1H, doublet, J=8.79Hz); 6.86 (1H, doublet, J=1.95 Hz); 6.98-7.05 (2H, multiplet); 7.14-7.30(2H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1595, 1580, 1515, 1470, 1260, 1175, 1145, 1130.

Mass Spectrum (m/z): 326 (M⁺), 284, 267, 239.

PREPARATION 101

(Z)-3-(3-methoxy-4-propoxyphenyl)-3-(3-methylphenyl)acrylic acid

Prepared as crystals, melting at 132°-135° C. (after recrystallizationfrom a mixture of methylene chloride and hexane), in a yield of 97%.

PREPARATION 102

Ethyl 3,3-bis(3-methylphenyl)acrylate

Prepared as an oil, in a yield of 78%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.11 (3H,triplet, J=7.32 Hz); 2.32 (3H, singlet); 2.35 (3H, singlet); 4.03 (2H,quartet, J=7.32 Hz); 6.31 (1H, singlet); 6.98-7.30 (8H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1620, 1600,1580, 1370, 1350, 1280, 1190, 1160.

Mass Spectrum (m/z): 280 (M⁺), 265, 251, 235, 208.

PREPARATION 103

3,3-Bis(3-methylphenyl)acrylic acid

Prepared as crystals, melting at 133°-135° C. (after recrystallizationfrom a mixture of methylene chloride and hexane), in a yield of 94%.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.32 (3H,singlet); 2.34 (3H, singlet); 6.28 (1H, singlet); 6.98-7.12 (4H,multiplet); 7.14-7.30 (4H, multiplet).

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1690, 1615, 1600, 1580, 1430, 1285, 1170.

Mass Spectrum (m/z): 252 (M⁺), 237, 235, 207.

PREPARATION 104

Methyl (E)-3,5-diphenylpent-2-en-4-ynoate

0.158 g of cuprous iodide and 0.424 g of phenylacetylene were added to25 ml of a diethylamine solution containing 1.000 g of methyl(Z)-3-bromocinnamate and 0.029 g ofbis(triphenylphosphine)dichloropalladium. The mixture was then stirredfor 1 hour at room temperature, after which the solvent was distilledoff under reduced pressure. Water was added to the residue, and theresulting mixture was extracted twice with benzene. The combined benzeneextracts were washed with water, dried over anhydrous sodium sulfate andcondensed by evaporation under reduced pressure. The residue wassubjected to column chromatography through silica gel (70-230 Tylermesh, 25 g). Those fractions eluted with a 39:1 by volume mixture ofhexane and ethyl acetate were collected to afford 1.043 g of the titlecompound, melting at 73°-75° C. (after recrystallisation from hexane).

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 3.84 (3H,singlet); 6.60 (1H, singlet); 7.34-7.82 (10H, multiplet).

Mass spectrum (m/z): 262 (M⁺); 247, 231.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2200, 1710, 1600,1590, 1575, 1490, 1450, 1435, 1365, 1275, 1165.

PREPARATION 105

(E)-3,5-Diphenylpent-2-en-4-ynoic acid

A mixture of 1.000 g of methyl (E)-3,5-diphenylpent-2-en-4-ynoate(prepared as described in Preparation 104), 15 ml of methanol, 7.5 ml oftetrahydrofuran and 15 ml of a 10% w/v aqueous solution of sodiumhydroxide was stirred for 18 hours at room temperature. At the end ofthis time, the solvent was distilled off under reduced pressure. Theresulting residue was diluted with water and extracted twice withdiethyl ether. The ethereal extracts were washed with water, dried overanhydrous sodium sulfate and condensed by evaporation under reducedpressure, to give 0.912 g of the title compound, melting at 124°-126° C.(after recrystallisation from a mixture of methylene chloride andhexane).

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 6.65 (1H,singlet); 7.30-7.90 (10H, multiplet).

Mass spectrum (m/z): 248 (M⁺), 231, 220.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),2200, 1685, 1600, 1590, 1575, 1490, 1450, 1280, 1180.

PREPARATION 106

Ethyl 3,3-bis(4-methoxyphenyl)-3-hydroxy-2-methylpropionate

A mixture of 8.25 g of ethyl 2-bromopropionate, 11.81 g of4,4'-dimethoxybenzophenone, 7.16 g of zinc and 70 ml of benzene washeated on an oil bath for 4 hours under reflux. The mixture was thenallowed to stand to cool, after which the reaction solution wasfiltered. The filtrate was washed with 10% w/v aqueous sulfuric acid,with water and with a saturated aqueous solution of sodium chloride, inthat order. After the mixture had been dried, the solvent was distilledoff under reduced pressure. The residue was subjected to flash columnchromatography through silica gel (about 400 mesh, 300 g). 7.92 g of thetitle compound were obtained as white crystals, melting at 67°-69° C.(after recrystallisation from a mixture of methylene chloride andhexane), from those fractions eluted with a 100:2 ny volume mixture ofhexane and ethyl acetate.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 1.14 (6H,triplet, J=6.84 Hz); 3.54 (1H, quartet, J=6.84 Hz); 3.75 (6H, singlet);3.95-4.15 (2H, multiplet); 4.61 (1H, singlet); 6.80 (4H, doublet ofmultiplets, J=8.79 Hz); 7.33 (2H, doublet of multiplets, J=8.79 Hz);7.44 (2H, doublet of multiplets, J=8.79 Hz).

Mass spectrum (m/z): 344 (M⁺), 326, 299, 281, 243.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1710, 1610, 1510,1460, 1375, 1340, 1245, 1170.

Elemental analysis: Calculated for C₂₀ H₂₄ O₅ : C, 69.75%; H, 7.02%.Found: C, 69.89%; H, 7.10%.

PREPARATION 107

Ethyl 3,3-bis(4-methoxyphenyl)-2-methylacrylate

4.10 ml of phosphorus oxychloride were dropped at from 5° to 10° C. onto140 ml of a benzene solution containing 7.02 g of ethyl3,3-bis(4-methoxyphenyl)-3-hydroxy-2-methylpropionate (prepared asdescribed in Preparation 106) on an ice bath. The reaction solution wasthen stirred for 3 hours at room temperature, after which it was pouredinto water and then extracted with diethyl ether three times. Thecombined ethereal extracts were washed with a saturated aqueous solutionof sodium bicarbonate, with water and with a saturated aqueous solutionof sodium chloride, after which it was dried over anhydrous sodiumsulfate and condensed by evaporation under reduced pressure. The residue(6.72 g) was subjected to flash column chromatography through 100 g ofsilica gel. 6.04 g of the title compound were obtained as an oilysubstance from those fractions eluted with a 95:5 by volume mixture ofhexane and ethyl acetate.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 0.95 (3H,triplet, J=7.32 Hz); 2.05 (3H, singlet); 3.78 (3H, singlet); 3.81 (2H,singlet); 3.97 (2H, quartet, J=7.32 Hz); 6.79 (2H, doublet ofmultiplets, J=8.30 Hz); 6.85 (2H, doublet of multiplets, J=8.30 Hz);7.03 (2H, doublet of multiplets, J=8.30 Hz); 7.08 (2H, doublet ofmultiplets, J=8.30 Hz).

Mass spectrum (m/z): 326 (M⁺), 297, 281, 271, 252.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 1700, 1610, 1510,1465, 1315, 1300, 1280, 1240, 1175, 1125.

Elemental analysis: Calculated for C₂₀ H₂₂ O₄ : C, 73.60%; H, 6.79%.Found: C, 73.39%; H, 6.82%.

PREPARATION 108

3,3-Bis(4-methoxyphenyl)-2-methylacrylic acid

A mixture of 6.019 g of ethyl 3,3-bis(4-methoxyphenyl)acrylate (preparedas described in Preparation 107), 120 ml of ethanol and 80 ml of a 10%w/v aqueous solution of sodium hydroxide was stirred for 14 hours atroom temperature. At the end of this time, the reaction mixture washeated on an oil bath at 100° C. for 4 hours, and then ethanol wasdistilled off. The residue was diluted with ice-water and washed withethyl acetate. Concentrated hydrochloric acid was dropped onto theaqueous phase on an ice bath, to adjust the pH to a value of 2. Theaqueous phase was extracted twice with methylene chloride. The combinedmethylene chloride extracts were washed with water, dried over anhydroussodium sulfate and condensed by evaporation under reduced pressure, toafford 5.117 g of the title compound as white crystals, melting at134°-135° C. (after recrystallisation from a mixture of methylenechloride and hexane).

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.06 (3H,singlet); 3.80 (3H, singlet); 3.81 (3H, singlet); 6.79 (2H, doublet ofmultiplets, J=8.79 Hz); 6.86 (2H, doublet of multiplets, J=8.79 Hz);7.06 (2H, doublet of multiplets, J=8.79 Hz); 7.07 (2H, doublet ofmultiplets, J=8.79 Hz).

Mass spectrum (m/z): 298 (M⁺), 281, 253.

Infrared Absorption Spectrum (CHCl₃) ν_(max) cm⁻¹ : 2400-3600 (broad),1680, 1610, 1510, 1245, 1175.

Elemental analysis: Calculated for C₁₈ H₁₈ O₄ : C, 72.47%; H, 6.08%.Found: C, 72.11%; H, 6.15%.

PREPARATION 109

N-(3,4,5-Trimethoxybenzenesulfonyl)piperazine

75 ml of a methylene chloride solution containing 7.40 g of3,4,5-trimethoxybenzenesulfonyl chloride were dropped into 150 ml of amethylene chloride solution containing 3.80 g of N-formylpiperazine and7.73 ml of triethylamine in an ice bath. The mixture was then stirredfor 30 minutes at 0° to 5° C., after which it was poured into water andextracted twice with methylene chloride. The combined methylene chlorideextracts were washed with 10% w/v aqueous hydrochloric acid and with asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate and condensed by evaporation under reduced pressure. Theresidue (9.86 g) was dissolved in a mixture of 150 ml oftetrahydrofuran, 75 ml of methanol and 50 ml of a 10% w/v aqueoussolution of sodium hydroxide, and then stirred for 14 hours at roomtemperature. At the end of this time, the reaction solution was pouredinto water and extracted 4 times with methylene chloride. The combinedmethylene chloride extracts were washed with water, dried over anhydroussodium sulfate and condensed by evaporation under reduced pressure. Theresidue was crystallized from a mixture of hexane and ethyl acetate, togive 7.02 g of the title compound as crylstals, melting at 131° to 133°C.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm: 2.90-3.10(8H, multiplet); 3.91 (9H, singlet); 6.96 (2H, singlet).

Mass spectrum (m/z): 316 (M⁺), 232, 85.

Elemental analysis: Calculated for C₁₃ H₂₀ N₂ O₅ S: C, 49.35%; H, 6.37%;N, 8.85%; S, 10.13%. Found: C, 49.62%; H, 6.30%; N, 8.55%; S, 10.11%.

PREPARATION 110

3,3-Bis(3-chlorophenyl)acrylic acid

Following a procedure similar to that described in Preparation 1, butusing 10.85 g of 3,3'-dichlorobenzophenone, 12.32 g of the titlecompound, melting at 114°-115° C., were obtained after recrystallizationfrom a mixture of methylene chloride and hexane.

PREPARATION 111

1-[3,3-Bis(3-chlorophenyl)acryloyl]piperazine

5.51 ml of diphenylphosphoryl azide and 1.93 ml of N-formylpiperazinewere added, in that order, to 100 ml of a methylene chloride solutioncontaining 5.00 g of 3,3-bis(3-chlorophenyl)acrylic acid (prepared asdescribed in Preparation 110) and 4.75 ml of triethylamine. The reactionmixture was then stirred at room temperature for 18 hours, after whichit was washed with a saturated aqueous solution of sodium bicarbonateand then with water. It was then dried over anhydrous sodium sulfate andthe solvent was removed by distillation under reduced pressure. Theresidue was dissolved in a mixture of 100 ml of ethanol and 50 ml oftetrahydrofuran, and 50 ml of a 10% w/v aqueous solution of sodiumhydroxide were added. The resulting mixture was stirred for 8 hours atroom temperature, after which it was poured into water. The solution wasextracted twice, each time with methylene chloride, and the combinedextracts were washed with water and dried over anhydrous sodium sulfate;the solvent was then removed by distillation under reduced pressure. Theresulting residue was purified by column chromatography through 150 g ofsilica gel, using mixtures of methylene chloride and methanol rangingfrom 49:1 to 9:1 by volume as eluent, to give 5.23 g of the titlecompound as a viscous oil.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 2.21 (1H,singlet); 2.00-2.95 (4H, multiplet); 3.00-3.85 (4H, multiplet); 6.38(1H, singlet); 6.90-7.50 (8H, multiplet).

Mass Spectrum (m/z): 360 (M⁺, ³⁵ Cl), 325, 292, 275.

PREPARATION 112

Ethyl (Z) and (E)-3-(2-naphthyl)-3-phenylacrylate

A procedure similar to that described in the first half of Preparation 1was repeated, except that 10.10 g of β-naphthyl phenyl ketone were used.The resulting crude compound was purified by column chromatographythrough 200 g of silica gel and then by medium pressure liquidchromatography through a Lobar C column, eluted with mixtures of hexaneand ethyl acetate, to give 2.48 g of the Z-isomer of the title compound,melting at 91°-92° C., after recrystallization from hexane.

Further elution with the same solvent gave 4.44 g of the E-isomer,melting at 84°-85° C., after recrystallization from hexane.

PREPARATION 113

(Z)-3-(2-Naphthyl)-3-phenylacrylic acid

24 ml of a 10% w/v aqueous solution of sodium hydroxide were added to asolution of 2.411 g of ethyl (Z)-3-(2-naphthyl)-3-phenylacrylate(prepared as described in Preparation 112) in 48 ml of ethanol and 24 mlof tetrahydrofuran. The mixture was stirred for 15 hours at roomtemperature and then poured into water. The pH of the resulting mixturewas adjusted to a value of 2 by the addition of concentratedhydrochloric acid, and the mixture was then extracted twice withmethylene chloride. The combined extracts were washed with water anddried over anhydrous sodium sulfate; the solvent was then removed byevaporation under reduced pressure. The residue was recrystallized froma mixture of methylene chloride and hexane, to give 2.005 g of the titlecopound, melting at 170°-172° C.

Nuclear Magnetic Resonance Spectrum (a 1:1 by volume mixture of CDCl₃and CD₃ OD, 60 MHz) δ ppm: 6.44 (1H, singlet); 7.28-7.42 (6H,multiplet); 7.44-7.54 (2H, multiplet); 7.71 (1H, doublet, J=0.73 Hz);7.76-7.91 (3H, multiplet).

Mass Spectrum (m/z): 274 (M⁺), 257, 229.

Elemental analysis: Calculated for C₁₉ H₁₄ O₂ : C, 83.19%; H, 5.14%.Found: C, 83.39%; H, 5.35%.

PREPARATION 114

(E)-3-(2-Naphthyl)-3-phenylacrylic acid

A hydrolysis procedure similar to that described in Preparation 113 wasrepeated, except that 2.219 g of ethyl(E)-3-(2-naphthyl)-3-phenylacrylate (prepared as described inPreparation 112) were used, to give 1.685 g of the title compound,melting at 229°-231° C., after recrystallization from a mixture ofdiethyl ether and tetrahydrofuran.

Nuclear Magnetic Resonance Spectrum (a 1:1 by volume mixture of CDCl₃and CD₃ OD, 60 MHz) δ ppm: 6.50 (1H, singlet); 7.23-7.32 (2H,multiplet); 7.36-7.43 (3H, multiplet); 7.43-7.54 (3H, multiplet); 7.67(1H, doublet, J=1.83 Hz); 7.70-7.88 (3H, multiplet).

Mass Spectrum (m/z): 274 (M⁺), 257, 229.

Elemental analysis: Calculated for C₁₉ H₁₄ O₂ : C, 83.19%; H, 5.14%.Found: C, 83.45%; H, 5.33%.

PREPARATION 115

Ethyl (E)-p-isobutoxycinnamate

13.8 g of potassium carbonate and 7.50 g of sodium iodide were added toa solution of 9.61 g of ethyl (E)-p-hydroxycinnamate and 8.22 g ofisobutylbromide in 100 ml of dimethyl sulfoxide. The reaction mixturewas then stirred for 20 hours at 60° C., after which it was cooled tothe room temperature. The reaction mixture was then poured into 1 literof water and extracted twice with ethyl acetate. The combined extractswere washed with water and dried over anhydrous sodium sulfate; thesolvent was then removed by evaporation under reduced pressure. Theresidue was purified by flash column chromatography using 300 g ofsilica gel, eluted with a 5:1 by volume solution of hexane and ethylacetate, to give 10.71 g of the title compound as a colorless oil (whichsolidified at low temperature).

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 0.98 (6H,doublet, J=7 Hz); 1.28 (3H, triplet, J=7 Hz); 1.60-2.50 (1H, multiplet);3.70 (2H, doublet, J=7 Hz); 4.24 (2H, quartet, J=7 Hz); 6.26 (1H,doublet, J=16 Hz); 6.86 (2H, doublet of multiplets, J=9 Hz); 7.45 (2H,doublet of multiplets, J=9 Hz); 7.66 (1H, doublet, J=16 Hz).

PREPARATION 116

Ethyl (E)-p-propoxycinnamate

Following a procedure similar to that described in Preparation 115, butusing 9.61 g of ethyl (E)-p-hydroxycinnamate and 10.20 g of propyliodide and not using sodium iodide, 11.00 g of the title compound wereobtained as a solid material.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 0.98 (3H,triplet, J=7 Hz); 1.26 (3H, triplet, J=7 Hz); 1.20-2.20 (2H, multiplet);3.88 (2H, triplet, J=6.5 Hz); 4.21 (2H, quartet, J=7 Hz); 6.24 (1H,doublet, J=16 Hz); 6.85 (2H, doublet of multiplets, J=8 Hz); 7.44 (2H,doublet of multiplets, J=8 Hz); 7.62 (1H, doublet, J=16 Hz).

PREPARATION 117

Ethyl (E)-3,4-dipropoxycinnamate

Following a procedure similar to that described in Preparation 116, butusing 10.41 g of ethyl (E)-3,4-dihydroxycinnamate and 20.40 g of propyliodide, 10.20 g of the title compound were obtained as a solid material.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 1.02 (6H,triplet, J=7 Hz); 1.32 (3H, triplet, J=7 Hz); 1.50-2.20 (4H, multiplet);3.99 (4H, triplet, J=7 Hz); 4.26 (2H, quartet, J=7 Hz); 6.30 (1H,doublet, J=16 Hz); 6.70-7.35 (3H, multiplet); 7.65 (1H, doublet, J=16Hz).

PREPARATION 118

Ethyl (E)-4-ethoxy-3-methoxycinnamate

Following a procedure similar to that described in Preparation 116, butusing 5.83 g of ethyl (E)-4-hydroxy-3-methoxycinnamate and 5.61 g ofethyl iodide, 5.55 g of the title compound were obtained as a solidmaterial.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 1.30 (3H,triplet, J=7 Hz); 1.44 (3H, triplet, J=7 Hz); 3.89 (3H, singlet); 4.14(2H, quartet, J=7 Hz); 4.24 (2H, quartet, J=7 Hz); 6.30 (1H, doublet,J=16 Hz); 6.75-7.35 (3H, multiplet); 7.66 (1H, doublet, J=7 Hz).

PREPARATION 119

Ethyl (E)-3-methoxy-4-propoxycinnamate

Following a procedure similar to that described in Preparation 116, butusing 11.11 g of ethyl (E)-4-hydroxy-3-methoxycinnamate and 10.20 g ofpropyl iodide, 12.08 g of the title compound were obtained.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 1.01 (3H,triplet, J=7 Hz); 1.30 (3H, triplet, J=7 Hz); 1.50-2.20 (2H, multiplet);3.88 (3H, singlet); 3.98 (2H, triplet, J=7 Hz); 4.24 (2H, quartet, J=7Hz); 6.28 (1H, doublet, J=16 Hz); 6.70-7.35 (3H, multiplet); 7.65 (1H,doublet, J=16 Hz).

PREPARATION 120

Ethyl (E)-4-butoxy-3-methoxycinnamate

Following a procedure similar to that described in Preparation 116, butusing 6.66 g of ethyl (E)-4-hydroxy-3-methoxycinnamate and 6.62 g ofbutyl iodide, 7.00 g of the title compound were obtained as a solidmaterial.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz) δ ppm: 0.96 (3H,triplet, J=7 Hz); 1.30 (3H, triplet, J=7 Hz); 1.20-2.10 (4H, multiplet);3.88 (3H, singlet); 4.03 (3H, triplet, J=7 Hz); 4.24 (2H, quartet, J=7Hz); 6.28 (1H, doublet, J=16 Hz); 6.75-7.35 (3H, multiplet); 7.65 (1H,doublet, J=16 Hz).

PREPARATION 121

Ethyl (Z)-3-(3-Propoxyphenyl)-3-(3-chlorophenyl)acrylate

Prepared as an oil, in a yield of 10%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.02(3H,t,J=7.33 Hz), 1.12(3H,t,J=7.33 Hz), 1.70-1.85(2H,m),3.88(2H,t,J=6.84 Hz), 4.06 (2H,q,J=7.33 Hz), 6.37(1H,s),6.80-6.86(2H,q,J=7.33 Hz), 6.37(1H,s), 6.80-6.86(2H,m),6.90(1H,ddd,J=8.30,2.44, 0.97 Hz), 7.10(1H,ddd,J=6.84,1.47,1.47 Hz),7.19-7.38(4H,m).

Mass Spectrum (m/z): 344(M⁺,³⁵ Cl), 302, 299.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1620, 1600,1580, 1485, 1475, 1440, 1370, 1350, 1290, 1170.

PREPARATION 122

Ethyl (E)-3-(3-Propoxyphenyl)-3-(3-chlorophenyl)acrylate

Prepared as an oil, in a yield of 18%

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.02(3H,t,J=7.33 Hz), 1.12(3H,t,J=7.32 Hz), 1.70-1.90(2H,m),3.89(2H,t,J=6.84 Hz), 4.06 (2H,q,J=7.33 Hz), 6.32(1H,s), 6.71(1H,m),6.77(1H,ddd,J=7.81,1.46, 0.98 Hz), 6.92(1H,ddd,J=8.30,2.93,0.98 Hz),7.16-7.35(5H,m).

Mass Spectrum (m/z): 344(M⁺,³⁵ Cl), 302, 299.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1600, 1580,1570, 1475, 1440, 1370, 1350, 1280, 1260, 1170, 1030.

PREPARATION 123

(Z)-3-(3-Propoxyphenyl)-3-(3-chlorophenyl)acrylic acid

Prepared as crystals, melting at 118°-120° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 94%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.02(3H,t,J=7.33 Hz), 1.70-1.90(2H,m), 3.88(2H,t,J=6.84 Hz), 6.34(1H,s),6.77-6.85(2H, m), 6.92(1H,ddd,J=7.32,2.44,0.98 Hz),7.10(1H,ddd,J=7.31,1.46,1.46 Hz), 7.17-7.38(4H,m).

Mass Spectrum (m/z): 316(M⁺, ³⁵ Cl), 274, 257.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1695, 1620, 1600,1580, 1490, 1480, 1440, 1410, 1350, 1290, 1150.

PREPARATION 124

Ethyl (Z)-3-(4-Propoxyphenyl)-3-(3-chlorophenyl)acrylate

Prepared as an oil, in a yield of 10%

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.03(3H,t,J=7.32 Hz), 1.12(3H,t,J=7.32 Hz), 1.75-1.90(2H,m),3.95(2H,t,J=6.84 Hz), 4.04(2H,q,J=7.32 Hz), 6.31(1H,s), 6.84(2H,dm,J=8.79 Hz), 7.09(1H,ddd,J=6.84, 1.95,1.95 Hz), 7.17-7.20(1H,m),7.21(2H,dm,J=8.79 Hz), 7.28-7.40(2H,m).

Mass Spectrum (m/z): 344(M⁺, ³⁵ Cl), 302, 299.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1600, 1590,1570, 1510, 1470, 1370, 1275, 1255, 1170, 1155.

PREPARATION 125

Ethyl (E)-3-(4-Propoxyphenyl)-3-(3-chlorophenyl)acrylate

Prepared as an oil, in a yield of 14%

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.05(3H,t,J=7.32 Hz), 1.17(3H,t,J=7.32 Hz), 1.75-1.90(2H,m),3.95(2H,t,J=6.84 Hz), 4.09(2H,q,J=7.32 Hz), 6.24(1H,s),6.89(2H,dm,J=8.79 Hz), 7.12(1H,dm,J=8.79 Hz),7.17(1H,ddd,J=7.81,1.95,1.95 Hz), 7.25(1H,dd, J=7.81,7.81 Hz),7.28(1H,dd, J=1.95,1.95 Hz), 7.33(1H,ddd,J=7.81,1.95,1.95 Hz).

Mass Spectrum (m/z): 344(M⁺, ³⁵ Cl), 302, 299.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1610, 1510,1470, 1290, 1240, 1170.

PREPARATION 126

(Z)-3-(4-Propoxyphenyl)-3-(3-chlorophenyl)acrylic acid

Prepared as crystals, melting at 174.5°-176.5° C. (afterrecrystallisation from a mixture of methylene chloride and hexane), in ayield of 92%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.03(3H,t,J=7.32 Hz), 1.74-1.90(2H,m), 3.93(2H,t,J=6.83 Hz), 6.29(1H,s),6.84(2H,dm,J=9.28 Hz), 7.09(1H,ddd,J=7.33,1.95,1.95 Hz),7.16-7.20(1H,m), 7.20(2H,dm,J=9.28 Hz), 7.27-7.38(2H,m).

Mass Spectrum (m/z): 316(M⁺, ³⁵ Cl), 274, 257, 229.

Infrared Absorption Spectrum ν_(max) (KBr) cm⁻¹ : 3400-2400, 1665, 1600,1585, 1510, 1305, 1260, 1245, 1180.

PREPARATION 127

(E)-3-(4-Propoxyphenyl)-3-(3-chlorophenyl)acrylic acid

Prepared as crystals, melting at 147°-149° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 95%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.06(3H,t,J=7.32 Hz), 1.75-1.90(2H,m), 3.96(2H,t,J=6.34 Hz), 6.20(1H,s),6.88(2H,dm,J=8.79 Hz), 7.14(2H,dm,J=8.79 Hz), 7.14-7.19(1H,m),7.23-7.38(3H,m).

Mass Spectrum (m/z): 316(M⁺, ³⁵ Cl), 274, 257, 229.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3600-2400, 1690,1610, 1570, 1515, 1290, 1250, 1180.

PREPARATION 128

Ethyl (Z)-3-(2-Chlorophenyl)-3-(3-methoxyphenyl)acrylate

Prepared as crystals, melting at 82°-84° C. (after recrystallisationfrom a mixture of ethyl ether and hexane), in a yield of 63%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.10(3H,t,J=7.32 Hz), 3.78(3H,s), 4.04(2H,q,J=7.32 Hz), 6.54(1H,s),6.84-6.94(3H,m), 7.14-7.19(1H,m), 7.21-7.36(3H,m), 7.40-7.48(1H,m).

Mass Spectrum (m/z): 316(M⁺, ³⁵ Cl), 281, 271, 253.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1715, 1615, 1600,1580, 1490, 1470, 1435, 1370, 1350, 1290, 1170, 1050, 1035.

PREPARATION 129

(Z)-3-(2-Chlorophenyl)-3-(3-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 140°-142° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 96%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.77(3H,s),6.51(1H,s), 6.83(1H,dd,J=1.95,1.95 Hz), 6.86-6.94(2H,m),7.11-7.18(1H,m), 7.21-7.35(3H,m), 7.38-7.46(1H,m).

Mass Spectrum (m/z): 288(M⁺, ³⁵ Cl), 253.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3600-2400, 1695,1625, 1600, 1580, 1490, 1470, 1430, 1290, 1050.

PREPARATION 130

Ethyl (Z)-3-(4-Methoxyphenyl)-3-(3-bromophenyl)acrylate

Prepared as an oil, in a yield of 9%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.12(3H,t,J=7.32 Hz), 3.82(3H,s), 4.05(2H,q,J=7.32 Hz), 6.31(1H,s),6.85(2H,dm,J=8.79 Hz), 7.14(1H,ddd,J=7.81,1.47,1.47 Hz),7.22(2H,dm,J=8.79 Hz), 7.25(1H,ddd,J=7.81,7.81,1.47 Hz),7.35(1H,dd,J=1.47,1.47 Hz), 7.51(1H,ddd,J=7.81,1.47, 1.47 Hz).

Mass Spectrum (m/z): 360(M⁺, ⁷⁹ Br), 333, 315, 288.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1600, 1510,1370, 1290, 1270, 1250, 1165, 1025, 830.

PREPARATION 131

Ethyl (E)-3-(4-Methoxyphenyl)-3-(3-bromophenyl)acrylate

Prepared as an oil, in a yield of 12%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.17(3H,t,J=7.32 Hz), 3.84(3H,s), 4.09(2H,q,J=7.32 Hz), 6.24(1H,s),6.90(2H,dm,J=8.79 Hz), 7.14(2H,dm,J=8.79 Hz), 7.18-7.24(2H,m),7.43-7.52(2H,m).

Mass Spectrum (m/z): 360(M⁺,⁷⁹ Br), 333, 315, 288.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1715, 1610, 1515,1375, 1295, 1250, 1175, 1030, 840.

PREPARATION 132

(Z)-3-(4-Methoxyphenyl)-3-(3-bromophenyl)acrylic acid

Prepared as crystals, melting at 169°-171° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 97%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.82(3H,s),6.29(1H,s), 6.85(2H,dm,J=9.28 Hz), 7.14(1H,ddd,J=7.81, 1.95, 0.98 Hz),7.21(2H,dm,J=9.28 Hz), 7.25(1H,dd,J=7.81,7.81 Hz), 7.33(1H,dd,J=1.95,1.95 Hz), 7.51(1H,ddd,J=7.81, 1.95, 0.98 Hz).

Mass Spectrum (m/z): 332(M⁺,⁷⁹ Br), 315.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 2400-3600, 1685,1595, 1570, 1555, 1505, 1420, 1275, 1250, 1170, 1020, 825.

PREPARATION 133

(E)-3-(4-Methoxyphenyl)-3-(3-bromophenyl)acrylic acid

Prepared as crystals, melting at 131°-132° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 96%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.82(3H,s),6.20(1H,s), 6.90(2H,dm,J=8.79 Hz), 7.15(2H,dm,J=8.79 Hz),7.18-7.24(2H,m), 7.40-7.44(1H,m), 7.46-7.54(1H,m).

Mass Spectrum (m/z): 332(M⁺,⁷⁹ Br), 315.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 2400-3600, 1690,1610, 1560, 1510, 1470, 1420, 1295, 1245, 1175, 1030, 835.

PREPARATION 134

Ethyl (Z)-3-(3-Fluorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil, in a yield of 55%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.12(3H,t,J=7.33 Hz), 3.82(3H,s), 4.04(2H,q,J=7.33 Hz), 6.32(1H,s),6.85(2H,dm,J=8.79 Hz), 6.91(1H,ddd,J=9.53, 2.57, 1.47 Hz),6.99(1H,dm,J=7.69 Hz), 7.03-7.11(1H,m), 7.23(2H,dm,J=8.79 Hz),7.35(1H,ddd,J=7.69, 7.69, 5.87 Hz).

Mass Spectrum (m/z): 300(M⁺), 271, 255, 228.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1705, 1600, 1585,1510, 1440, 1370, 1275, 1250, 1160, 1030, 830.

PREPARATION 135

Ethyl (E)-3-(3-Fluorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil, in a yield of 22%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.17(3H,t,J=7.32 Hz), 3.84(3H,s), 4.09(2H,q,J=7.32 Hz), 6.27(1H,s),6.91(2H,dm,J=8.79 Hz), 6.98(1H,ddd,J=10.25, 2.44, 1.96 Hz),7.05(1H,dddd,J=8.30, 8.30, 2.44, 0.98 Hz), 7.08-7.12(1H,m),7.15(2H,dm,J=8.79 Hz), 7.29(1H,ddd,J=8.30, 8.30, 5.86 Hz).

Mass Spectrum (m/z): 300(M⁺), 271, 255, 228.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1610, 1585,1510, 1485, 1440, 1370, 1295, 1280, 1245, 1170, 1030, 1030, 870, 830.

PREPARATION 136

(Z)-3-(3-Fluorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 166°-167° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 96%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.82(3H,s),6.29(1H,s), 6.85(2H,dm,J=8.79 Hz), 6.91(1H,ddd,J=9.76, 2.44, 1.46 Hz),6.95-7.01(1H,m), 7.07(1H,dddd,J=8.30, 8.30, 2.44, 0.97 Hz),7.21(2H,dm,J=8.79 Hz), 7.33(1H,ddd,J=8.30, 8.30, 5.86 Hz).

Mass Spectrum (m/z): 272(M⁺), 255, 227.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 2400-3600, 1695,1600, 1515, 1440, 1285, 1255, 1180, 1120, 1035.

PREPARATION 137

(E)-3-(3-Fluorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 133°-135° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 95%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.85(3H,s),6.23(1H,s), 6.89(2H,dm,J=8.79 Hz),6.96(1H,ddd,J=9.77, 1.96, 1.96 Hz),7.02-7.12(2H,m), 7.15(2H,dm,J=8.79 Hz), 7.30(1H,ddd,J=8.30, 8.30, 5.86Hz).

Mass Spectrum (m/z): 272(M⁺), 255, 227.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 2400-3600, 1690,1610, 1580, 1510, 1485, 1440, 1290, 1245.

PREPARATION 138

Ethyl (Z)-3-(3-Trifluoromethylphenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil, in a yield of 56%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.08(3H,t,J=7.32 Hz), 3.82(3H,s), 4.03(2H,q,J=7.32 Hz), 6.37(1H,s),6.86(2H,dm,J=8.79 Hz), 7.21(2H,dm,J=8.79 Hz), 7.37-7.43(1H,m), 744-7.47(1H,m) 7.48-7.55(1H,m), 7.61-7.67(1H,m).

Mass Spectrum (m/z): 350(M⁺), 331, 321, 305, 278.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1600, 1510,1325, 1255, 1165, 1130, 1070, 1030.

PREPARATION 139

Ethyl (E)-3-(3-Trifluoromethylphenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil, in a yield of 15%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.18(3H,t,J=7.33 Hz), 3.85(3H,s), 4.11(2H,q,J=7.33 Hz), 6.28(1H,s),6.91(2H,dm,J=8.79 Hz), 7.15(2H,dm,J=8.79 Hz), 7.37-7.53(2H,m),7.56-7.64(2H,m).

Mass Spectrum (m/z): 350(M⁺), 331, 321, 305, 278.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1610, 1510,1370, 1330, 1295, 1245, 1170, 1150, 1130, 1070, 1030.

PREPARATION 140

(Z)-3-(3-Trifluoromethylphenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 165°-167° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 91%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.82(3H,s),6.33(1H,s), 6.86(2H,dm,J=8.79 Hz), 7.19(2H,dm,J=8.79 Hz),7.37(1H,br.d,J=7.82 Hz), 7.45(1H,br,s). 7.48(1H,br,dd,J=7.82, 7.82 Hz),7.63(1H,br,d,J=7.82 Hz).

Mass Spectrum (m/z): 322(M⁺), 305, 277, 263.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 2400-3600, 1690,1600, 1575, 1510, 1440, 1325, 1310, 1290, 1260, 1180, 1150, 1130, 1070.

PREPARATION 141

Ethyl (E)-3-(3-Propoxyphenyl)-3-phenylacrylate

Prepared as an oil, in a yield of 23%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.01(3H,t,J=7.32 Hz), 1.10(3H,t,J=7.32 Hz), 1.70-1.90(2H,m),3.87(2H,t,J=6.84 Hz), 4.04(2H,q,J=7.32 Hz), 6.35(1H,s), 6.82-6.92(3H,m),7.16-7.40(6H,m).

PREPARATION 142

Ethyl (Z)-3-(3-Propoxyphenyl)-3-phenylacrylate

Prepared as an oil, in a yield of 47%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.01(3H,t,J=7.32 Hz), 1.12(3H,t,J=7.32 Hz), 1.70-1.90(2H,m),3.89(2H,t,J=6.84 Hz), 4.06 (2H,q,J=7.32 Hz), 6.34(1H,s),6.72-6.96(3H,m), 7.23-7.38(6H,m).

PREPARATION 143

(E)-3-(3-Propoxyphenyl)-3-phenylacrylic acid

Prepared as crystal, melting at 120°-122° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 51%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.00(3H,t,J=7.33 Hz), 1.70-1.90(2H,m), 3.86(2H,t,J=6.70 Hz), 6.31(1H,s),6.78-6.85(2H,m), 6.88-6.94(1H,m), 7.16-7.28(3H,m), 7.28-7.40(3H,m).

Mass Spectrum (m/z): 282(M⁺), 240, 223.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 2400-3600, 1690,1610, 1600, 1580, 1485, 1440, 1400, 1285.

PREPARATION 144

(Z)-3-(3-Propoxyphenyl)-3-phenylacrylic acid

Prepared as crystals, melting at 120°-122° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 67%.

Nuclear Magnetic Resonance Spectrum (270 MHz), CDCl₃) δ ppm:1.01(3H,t,J=7.33 Hz), 1.70-1.90(2H,m), 3.89(2H,t,J=6.84 Hz), 6.31(1H,s),6.73(1H,dd,J=2.44,1.47 Hz), 6.78(1H,ddd,J=7.32, 1.47, 0.98 Hz),6.91(1H,ddd,J=8.30, 2.44, 0.98 Hz), 7.22-7.40(6H,m).

Mass Spectrum (m/z): 282(M⁺), 240, 223.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 2400-3600, 1680,1590, 1570, 1480, 1440, 1425, 1390, 1275, 1100.

PREPARATION 145

Ethyl (Z)-3-(3,5-Dichlorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as crystals, melting at 116°-118° C. (after recrystallisationfrom hexane), in a yield of 64%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.14(3H,t,J=7.32 Hz), 3.82(3H,s), 4.06(2H,q,J=7.32 Hz), 6.33(1H,s),6.86(2H,dm,J=8.79 Hz), 7.09(2H,d,J=1.83 Hz), 7.21(2H,dm,J=8.79 Hz),7.37(1H,t,J=1.83 Hz).

Mass Spectrum (m/z): 350(M⁺, ³⁵ Cl), 321, 305, 278.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1600, 1585,1560, 1510, 1370, 1345, 1290, 1270, 1250, 1170, 1160, 1030, 860, 830.

PREPARATION 146

Ethyl (E)-3-(3,5-Dichlorophenyl)-3- (methoxyphenyl)acrylate

Prepared as an oil, in a yield of 19%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.17(3H,t,J=7.32 Hz), 3.85(3H,s), 4.09(2H,q,J=7.32 Hz), 6.23(1H,s),6.91(2H,dm,J=8.79 Hz), 7.13(2H,dm,J=8.79 Hz), 7.16(2H,d,J=1.96 Hz),7.35(1H,t,J=1.96 Hz).

Mass Spectrum (m/z): 350(M⁺,³⁵ Cl), 321, 305, 278.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1610, 1580,1560, 1510, 1415, 1370, 1350, 1290, 1245, 1170, 1030, 860, 835.

PREPARATION 147

(Z)-3-(3,5-Dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystal, melting at 214°-216° C. (after recrystallisationfrom a mixture of THF and hexane), in a yield of 71%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.78(3H,s),6.37(1H,s), 6.94(2H,dm,J=8.79 Hz), 7.17(2H,d,J=1.95 Hz),7.23(2H,dm,J=8.79 Hz), 7.57(1H,t,J=1.95 Hz).

Mass Spectrum (m/z): 322(M⁺, ³⁵ Cl), 305, 277.

Infrared Absorption Spectrum ν_(max) (KBr) cm⁻¹ : 2400-3400, 1695, 1670,1600, 1580, 1560, 1510, 1290, 1260, 1215, 1185, 1170, 1035, 840, 800.

PREPARATION 148

(E)-3-(3,5-Dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 169°-171° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 80%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.85(3H,s),6.19(1H,s), 6.90(2H,dm,J=8.79 Hz), 7.13(2H,dm,J=8.79 Hz),7.14(2H,d,J=1.95 Hz), 7.36(1H,t,J=1.95 Hz).

Mass Spectrum (m/z): 322(M⁺, ³⁵ Cl), 305, 277.

Infrared Absorption Spectrum ν_(max) (KBr) cm⁻¹ : 2400-3400, 1700, 1675,1610, 1580, 1560, 1510, 1425, 1350, 1280, 1250, 1220, 1175, 1030, 850,835, 805.

PREPARATION 149

Ethyl (Z)-3-(2,4-Dichlorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil, in a yield of 83%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.14(3H,t,J=7.33 Hz), 3.81(3H, s), 4.05(2H,q,J=7.32 Hz), 6.48(1H, s),6.85(2H,dm,J=8.80 Hz), 7.09(1H,d,J=8.42 Hz), 7.24(2H,dm,J=8.80 Hz),7.30(1H,dd,J=8.42,1.84 Hz), 7.47(1H,d,J=1.84 Hz).

Mass Spectrum (m/z): 350(M⁺, ³⁵ Cl), 315, 305, 287.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1605, 1590,1510, 1280, 1255, 1170, 1030, 830.

PREPARATION 150

(Z)-3-(2,4-Dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 162°-164° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 90%.

NMR (270 MHz, CDCl₃) δ ppm: 3.81(3H,s), 6.44(1H,s), 6.85(2H, dm, J=8.79Hz), 7.07(1H,d,J=8.30 Hz), 7.22(2H,dm,J=8.79 Hz), 7.28(1H,dd,J=8.30,1.95 Hz), 7.45(1H,d,J=1.95 Hz).

Mass Spectrum (m/z): 322(M⁺, ³⁵ Cl), 287.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1700, 1600, 1590,1510, 1285, 1260, 1180, 1155, 830.

PREPARATION 151

Ethyl (Z)-3-(4-Methoxyphenyl)-3-(2,6-dichlorophenyl)acrylate

Prepared as crystals, melting at 119°-121° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 60%.

NMR (270 MHz, CDCl₃) δ ppm: 1.13(3H,t,J=7.33 Hz), 3.81(3H,s),4.06(2H,q,J=7.33 Hz), 6.56(1H,s), 6.87(2H,dm,J=9.28 Hz),7.22-7.34(1H,m), 7.30(2H,dm,J=9.27 Hz), 7.35-7.41(2H,m).

Mass Spectrum (m/z): 350(M⁺, ³⁵ Cl), 315, 305, 287.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1605, 1575,1510, 1430, 1290, 1275, 1255, 1160, 1025, 830.

PREPARATION 152

(Z)-3-(4-Methoxyphenyl)-3-(2,6-dichlorophenyl)acrylic acid

Prepared as crystals, melting at 222°-224° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 98%.

NMR (270 MHz, CDCl₃) δ ppm: 3.81(3H,s), 6.53(1H,s), 6.87(2H,dm,J=8.79Hz), 7.20-7.40(3H,m), 7.28(2H,dm,J=8.79 Hz).

Mass Spectrum (m/z): 322(M⁺, ³⁵ Cl), 307, 305, 287, 272.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 2400-3600, 1700,1600, 1575, 1515, 1430, 1290, 1260, 1180, 1160, 835.

PREPARATION 153

Ethyl (Z)-3-(2,5-Dichlorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as crystals, melting at 98°-100° C. (after recrystallisationfrom hexane), in a yield of 82%.

NMR (270 MHz, CDCl₃) δ ppm: 1.13(3H,t,J=7.32 Hz), 3.82(3H,s),4.05(2H,q,J=7.32 Hz), 6.47(1H,s), 6.86(2H,dm,J=8.79 Hz),7.15(1H,d,J=2.44 Hz), 7.25(2H,dm,J=8.79 Hz), 7.29(1H,dd,J=8.30,2.44 Hz),7.37(1H,d,J=8.30 Hz).

Mass Spectrum (m/z): 350(M⁺, ³⁵ Cl), 315, 305, 287.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1715, 1605, 1515,1470, 1295, 1280, 1260, 1170, 1165, 1100, 1030, 835.

PREPARATION 154

(Z)-3-(2,5-Dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 201°-203° C. (after recrystallisationfrom a mixture of THF and hexane), in a yield of 97%.

NMR (270 MHz, d₆ -DMSO) δ ppm: 3.77(3H,s), 6.53(1H,s), 6.94(2H,dm,J=8.79Hz), 7.25(2H,dm,J=8.79 Hz), 7.29(1H,d,J=2.44 Hz), 7.46(1H,dd,J=8.79,2.44Hz), 7.53(1H,d,J=8.79 Hz), 12.13(1H,br,s).

Mass Spectrum (m/z): 322(M⁺, ³⁵ Cl), 305, 287, 272.

Infrared Absorption Spectrum ν_(max) (KBr) cm⁻¹ : 2200-3300, 1690, 1595,1580, 1510, 1465, 1425, 1345, 1280, 1260, 1210, 1185, 1160, 1030, 835.

PREPARATION 155

Ethyl (Z)-3-(2,3-Dichlorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as crystals, melting at 88°-90° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 70%.

NMR (270 MHz, CDCl₃) δ ppm: 1.11(3H,t,J=7.32 Hz), 3.81(3H,s),4.03(2H,q,J=7.32 Hz), 6.47(1H,s), 7.07(1H,dd,J=7.70,1.47 Hz),7.20-7.40(3H,m), 7.49(1H,dd,J=8.06,1.47 Hz).

Mass Spectrum (m/z): 350(M⁺, ³⁵ Cl), 315, 305, 287.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1600, 1575,1510, 1455, 1410, 1370, 1350, 1280, 1255, 1160, 1030, 830.

PREPARATION 156

(Z)-3-(2,3-Dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 129°-131° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 89%.

NMR (270 MHz, CDCl₃) δ ppm: 3.81(3H,s), 6.44(1H,s), 6.85(2H,dm,J=8.78Hz), 7.05(1H,dd,J=7.81,1.47 Hz), 7.23(1H,dd,J=7.81,7.81 Hz),7.24(2H,dm,J=8.78 Hz), 7.47(1H,dd,J=7.81,1.47 Hz).

Mass Spectrum (m/z): 322(M⁺, ³⁵ Cl), 287.

PREPARATION 157

Ethyl (Z)-3-(3,5-Dimethylphenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil, in a yield of 57%.

NMR (270 MHz, CDCl₃) δ ppm: 1.11(3H,t,J=7.32 Hz), 2.31(6H,s),3.81(3H,s), 4.04(2H,q,J=7.32 Hz), 6.80(2H,br,s), 6.83(2H,dm,J=9.16 Hz),6.99(1H,t,J=0.73 Hz), 7.25(2H,dm, J=9.16 Hz).

Mass Spectrum (m/z): 310(M⁺), 281, 265, 238.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1610, 1510,1460, 1440, 1370, 1350, 1290, 1245, 1170, 1030, 850, 840.

PREPARATION 158

Ethyl (E)-3-(3,5-Dimethylphenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil, in a yield of 24%.

NMR (270 MHz, CDCl₃) δ ppm: 1.16(3H,t,J=7.32 Hz), 2.27(3H,s),2.28(3H,s), 3.84(3H,s), 4.08(2H,q,J=7.32 Hz), 6.24(1H,s),6.895(2H,dm,J=8.79 Hz), 6.904(2H,br,s), 6.99(1H,br,s), 7.15(2H,dm,J=8.79Hz).

Mass Spectrum (m/z): 310(M⁺), 281, 265, 238.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1610, 1510,1460, 1440, 1370, 1350, 1290, 1245, 1170, 1030, 850, 840.

PREPARATION 159

(Z)-3-(3,5-Dimethylphenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 156°-158° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 96%.

NMR (270 MHz, CDCl₃) δ ppm: 2.31(6H,s), 3.81(3H,s), 6.24(1H, s),6.82(2H,br,s), 6.84(2H,dm,J=8.78 Hz), 7.01(1H,br,s), 7.22(2H,dm,J=8.78Hz).

Mass Spectrum (m/z): 282(M⁺), 267, 237.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 2400-3600, 1690,1600, 1570, 1510, 1285, 1250, 1175, 1030, 835.

PREPARATION 160

(E)-3-(3,5-Dimethylphenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 165°-166° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 95%.

PREPARATION 161

Ethyl (E)-3-(3-Chlorophenyl)-3-(4-ethylphenyl)acrylate

Prepared as an oil, in a yield of 13%.

NMR (270 MHz, CDCl₃) δ ppm: 1.12(3H,t,J=7.33 Hz), 1.28(3H,t,J=7.69 Hz),2.70(2H,q,J=7.69 Hz), 4.07(2H,q,J=7.33 Hz), 6.29(1H,s), 7.11(2H,dm,J=8.43 Hz), 7.17(1H,ddd,J=7.69,2.20,1.47 Hz), 7.21(2H,dm,J=8.43 Hz),7.25(1H,dd,J=7.69,7.69 Hz), 7.29(1H,dd,J=1.47,1.47 Hz),7.32(1H,ddd,J=7.69,2.20,1.47 Hz).

Mass Spectrum (m/z): 314(M⁺, ³⁵ Cl), 285, 269, 242.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1610, 1570,1475, 1370, 1350, 1260, 1170, 1030, 875, 840.

PREPARATION 162

Ethyl (Z)-3-(3-Chlorophenyl)-3-(4-ethylphenyl)acrylate

Prepared as an oil, in a yield of 41%.

NMR (270 MHz, CDCl₃) δ ppm: 1.12(3H,t,J=7.32 Hz), 1.24(3H,t,J=7.69 Hz),2.66(2H,q,J=7.69 Hz), 6.36(1H,s), 7.10(1H,ddd,J=6.96,1.83,1.83 Hz,7.16(2H,dm,J=8.43 Hz), 7.18-7.21(1H,m), 7.21(2H,dm,J=8.43 Hz),7.27-7.34(1H,m), 7.35(1H,ddd,J=8.06,1.83,1.83 Hz).

Mass Spectrum (m/z): 314(M⁺, ³⁵ Cl), 285, 269, 242.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1620, 1610,1595, 1565, 1370, 1350, 1270, 1170, 1030, 830, 835.

PREPARATION 163

(E)-3-(3-Chlorophenyl)-3-(4-ethylphenyl)acrylic acid

Prepared as crystals, melting at 99°-100° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 95%.

NMR (270 MHz, CDCl₃) δ ppm: 1.28(3H,t,J=7.32 Hz), 2.70(2H,q,J=7.32 Hz),6.26(1H,s), 7.11(2H,dm,J=8.30 Hz), 7.15(1H,ddd,J=7.81,1.46,1.46 Hz),7.20(2H,dm,J=8.30 Hz), 7.26(1H,dd,J=7.81,7.81 Hz),7.34(1H,ddd,J=7.81,1.46,0.98 Hz).

Mass Spectrum (m/z): 286(M⁺, ³⁵ Cl), 271, 257, 241.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1690, 1610, 1570,1420, 1270, 1180, 840.

PREPARATION 164

(Z)-3-(3-Chlorophenyl)-3-(4-ethylphenyl)acrylic acid

Prepared as crystals, melting at 146°-148° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 96%.

NMR (270 MHz, CDCl₃) δ ppm: 1.23(3H,t,J=7.82 Hz), 2.66(2H,q,J=7.82 Hz),6.34(1H,s), 7.10(1H,ddd,J=6.84,1.47,1.47 Hz), 7.13-7.22(5H,m),7.27-7.34(1H,m), 7.35(1H,ddd,J=8.30,1.47,1.47 Hz).

Mass Spectrum (m/z): 286(M⁺,³⁵ Cl), 271, 257, 241.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1690, 1610, 1570,1420, 1270, 1180, 840.

PREPARATION 165

Ethyl (Z)-3-(3,5-Ditrifluoromethylphenyl)-3-(4-methoxyphenyl)acrylate

Prepared as crystals, melting at 104°-105° C. (after recrystallisationfrom a mixture of ethyl ether and hexane), in a yield of 62%.

NMR (270 MHz, CDCl₃) δ ppm: 1.08(3H,t,J=7.33 Hz), 3.83(3H,s),4.02(2H,q,J=7.33 Hz), 6.42(1H,s), 6.88(2H,dm,J=8.80 Hz),7.18(2H,dm,J=8.80 Hz), 7.64-7.69(2H,m), 7.88-7.92(1H,m).

Mass Spectrum (m/z): 418(M⁺), 399, 390, 373, 346.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1600, 1510,1460, 1390, 1330, 1280, 1175, 1140.

PREPARATION 166

Ethyl (E)-3-(3,5-Ditrifluoromethylphenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil, in a yield of 14%.

NMR (270 MHz, CDCl₃) δ ppm: 1.19(3H,t,J=7.33 Hz), 3.86(3H,s),4.12(2H,q,J=7.33 Hz), 6.31(1H,s), 6.93(2H,dm,J=8.79 Hz),7.14(2H,dm,J=8.79 Hz), 7.71-7.75(2H,m), 7.85-7.89(1H,m).

Mass Spectrum (m/z): 418(M⁺), 399, 389, 373, 346.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1720, 1610, 1515,1460, 1370, 1350, 1280, 1245, 1175, 1140.

PREPARATION 167

(Z)-3-(3,5-Ditrifluoromethylphenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 197°-199° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 92%.

NMR (270 MHz, CDCl₃) δ ppm: 3.83(3H,s), 6.40(1H,s), 6.88(2H,dm,J=8.79Hz), 7.18(2H,dm,J=8.79 Hz), 7.62-7.67(2H,m), 7.87-7.92(1H,m).

Mass Spectrum (m/z): 390(M⁺), 373, 345.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3700-2200, 1690,1600, 1510, 1460, 1420, 1390, 1330, 1280, 1180, 1140.

PREPARATION 168

(E)-3-(3,5-Ditrifluoromethylphenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 144°-146° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 95%.

NMR (270 MHz, CDCl₃) δ ppm: 3.87(3H,s), 6.27(1H,s), 6.93(2H,dm,J=8.79Hz), 7.16(2H,dm,J=8.79 Hz), 7.69-7.74(2H,m), 7.87-7.91(1H,m).

Mass Spectrum (m/z): 390(M⁺), 373, 345.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3200-2400, 1700,1610, 1515, 1460, 1380, 1350, 1280, 1250, 1180, 1140.

PREPARATION 169

Ethyl (Z)-3-(3,5-Dichlorophenyl)-3-(4-ethoxyphenyl)acrylate

Prepared as crystals, melting at 104°-106° C. (after recrystallisationfrom ethyl ether), in a yield of 41%.

NMR (270 MHz, CDCl₃) δ ppm: 1.14(3H,t,J=7.33 Hz), 1.42(3H,t,J=6.96 Hz),4.05(2H,q,J=6.96 Hz), 4.06(2H,q,J=7.33 Hz), 6.32(1H,s),6.85(2H,dm,J=8.79 Hz), 7.09(2H,d,J=1.83 Hz), 7.20(2H,dm,J=8.79 Hz),7.37(1H,t,J=1.83 Hz).

Mass Spectrum (m/z): 364(M⁺,³⁵ Cl), 319, 292.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1715, 1605, 1590,1565, 1515, 1370, 1350, 1275, 1255, 1160, 1040.

PREPARATION 170

Ethyl (E)-3-(3,5-Dichlorophenyl)-3-(4-ethoxyphenyl)acrylate

Prepared as an oil, in a yield of 12%.

NMR (270 MHz, CDCl₃) δ ppm: 1.17(3H,t,J=7.32 Hz), 1.44(3H,t,J=7.33 Hz),4.07(2H,q,J=7.33 Hz), 4.09(2H,q,J=7.32 Hz), 6.22(1H,s),6.90(2H,dm,J=8.79 Hz), 7.11(2H,dm,J=8.79 Hz), 7.16(2H,d,J=1.95 Hz),7.34(1H,t,J=1.95 Hz).

Mass Spectrum (m/z): 364(M⁺,³⁵ Cl), 319, 292.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1715, 1610, 1590,1560, 1515, 1395, 1370, 1350, 1290, 1245, 1175.

PREPARATION 171

(Z)-3-(3,5-Dichlorophenyl)-3-(4-ethoxyphenyl)acrylic acid

Prepared as crystals, melting at 220°-222° C. (after recrystallisationfrom a mixture of methanol and ethyl ether), in a yield of 86%.

NMR (270 MHz, DMSO-d₆) δ ppm: 1.32(3H,t,J=6.84 Hz), 4.04(2H,q,J=6.84Hz), 6.37(1H,s), 6.92(2H,dm,J=8.79 Hz), 7.18(2H,d,J=1.95 Hz),7.21(2H,dm,J=8.79 Hz), 7.60(1H,t,J=1.95 Hz), 12.18(1H,br.s).

Mass Spectrum (m/z): 336(M⁺, ³⁵ Cl), 308, 291.

Infrared Absorption Spectrum ν_(max) (KBr) cm⁻¹ : 3400-2200, 1695, 1670,1625, 1600, 1585, 1560, 1515, 1440, 1290, 1260, 1215, 1185, 1165, 840.

PREPARATION 172

(E)-3-(3,5-Dichlorophenyl)-3-(4-ethoxyphenyl)acrylic acid

Prepared as crystals, melting at 174°-176° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 89%.

NMR (270 MHz, CDCl₃) δ ppm: 1.44(3H,t,J=6.83 Hz), 4.08(2H,q,J=6.83 Hz),6.19(1H,s), 6.89(2H,dm,J=8.79 Hz), 7.12(2H,dm,J=8.79 Hz),7.15(2H,d,J=1.95 Hz), 7.36(1H,t,J=1.95 Hz).

Mass Spectrum (m/z): 336(M⁺, ³⁵ Cl), 308, 291.

Infrared Absorption Spectrum ν_(max) (CDCl₃) cm⁻¹ : 3600-2200, 1690,1610, 1585, 1560, 1510, 1420, 1390, 1290, 1245, 1175.

PREPARATION 173

Ethyl (Z)-3-(3,5-Dichlorophenyl)-3-(4-ethylphenyl)acrylate

Prepared as crystals, melting at 73°-75° C. (after recrystallisationfrom hexane), in a yield of 44%.

NMR (270 MHz, CDCl₃) δ ppm: 1.15(3H,t,J=7.32 Hz), 1.24(3H,t,J=7.32 Hz),2.66(2H,q,J=7.32 Hz), 4.07(2H,q,J=7.32 Hz), 6.38(1H,s), 7.10(2H,d,J=1.95Hz), 7.13-7.23(4H,m), 7.37(1H,t,J=1.95 Hz).

Mass Spectrum (m/z): 348(M⁺, ³⁵ Cl), 319, 303, 276.

Infrared Absorption Spectrum ν_(max) (CDCl₃) cm⁻¹ : 1710, 1620, 1605,1585, 1560, 1410, 1370, 1345, 1270, 1160.

PREPARATION 174

Ethyl (E)-3-(3,5-Dichlorophenyl)-3-(4-ethylphenyl)acrylate

Prepared as an oil, in a yield of 13%.

NMR (270 MHz, CDCl₃) δ ppm: 1.13(3H,t,J=7.32 Hz), 1.28(3H,t,J=7.32 Hz),2.70(2H,q,J=7.32 Hz), 4.07(2H,q,J=7.32 Hz), 6.27(1H,s),7.09(2H,dm,J=8.30 Hz), 7.17(2H,d,J=1.95 Hz), 7.22(2H,dm,J=8.30 Hz),7.34(1H,t,J=1.95 Hz).

Mass Spectrum (m/z): 348(M⁺, ³⁵ Cl), 319, 303, 276.

Infrared Absorption Spectrum ν_(max) (CDCl₃) cm-1: 1710, 1610, 1585,1560, 1410, 1370, 1350, 1260, 1170.

PREPARATION 175

(Z)-3-(3,5-Dichlorophenyl)-3-(4-ethylphenyl)acrylic acid

Prepared as crystals, melting at 206°-208° C. (after recrystallisationfrom a mixture of THF and hexane), in a yield of 90%.

NMR (270 MHz, DMSO-d₅) δ ppm: 1.17(3H,t,J=7.32 Hz), 2.61(2H,q,J=7.32Hz), 6.43(1H,s), 7.16-7.28(4H,m), 7.20(2H,d,J=1.95 Hz), 7.61(1H,t,J=1.95Hz), 12.32(1H,br,s).

Mass Spectrum (m/z): 320(M⁺, ³⁵ Cl), 291, 275.

Infrared Absorption Spectrum ν_(max) (KBr) cm⁻¹ : 3400-2200, 1695, 1670,1620, 1605, 1580, 1560, 1415, 1275, 1220, 835, 805.

PREPARATION 176

(E)-3-(3,5-Dichlorophenyl)-3-(4-ethylphenyl)acrylic acid

Prepared as crystals, melting at 162°-164° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 99%.

NMR (270 MHz, CDCl₃) δ ppm: 1.28(3H,t,J=7.32 Hz), 2.70(2H,q,J=7.32 Hz),6.23(1H,s), 7.09(2H,dm,J=8.30 Hz), 7.14(2H,d,J=1.95 Hz),7.21(2H,dm,J=8.30 Hz), 7.36(1H,t,J=1.95 Hz).

Mass Spectrum (m/z): 320(M⁺, ³⁵ Cl), 291, 275.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3600-2400, 1690,1610, 1595, 1560, 1415, 1265, 1180, 860, 835.

PREPARATION 177

Ethyl (Z)-3-(3,5-Difluorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as crystals, melting at 65°-66° C. (after recrystallisationfrom hexane), in a yield of 48%.

NMR (270 MHz, CDCl₃) δ ppm: 1.15(3H,t,J=7.32 Hz), 3.82(3H,s),4.07(2H,q,J=7.32 Hz), 6.33(1H,s), 6.69-6.89(3H,m), 6.86(2H,dm,J=9.16Hz), 7.22(2H,dm,J=9.16 Hz).

Mass Spectrum (m/z): 318(M⁺), 289, 273, 246.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1715, 1605, 1515,1435, 1375, 1290, 1255, 1170, 1120.

PREPARATION 178

Ethyl (E)-3-(3,5-Difluorophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil, in a yield of 20%.

NMR (270 MHz, CDCl₃) δ ppm: 1.17(3H,t,J=7.32 Hz), 3.85(3H,s),4.09(2H,q,J=7.32 Hz), 6.26(1H,s), 6.75-6.88(3H,m), 6.91(2H,dm,J=8.79Hz), 7.13(2H,dm,J=8.79 Hz).

Mass Spectrum (m/z): 318(M⁺), 289, 273, 246.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1715, 1620, 1610,1595, 1515, 1435, 1370, 1295, 1250, 1170, 1120.

PREPARATION 179

(Z)-3-(3,5-Difluorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 170°-172° C. (after recrystallisationfrom a mixture of THF and hexane), in a yield of 87%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.82(3H,s),6.30(1H,s), 6.67-6.90 (3H,m), 6.86(2H,dm,J=9.28 Hz), 7.21(2H,dm,J=9.28Hz).

Mass Spectrum (m/z): 2.90(M⁺), 273, 245.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3600-2400, 1695,1625, 1600, 1515, 1430, 1290, 1260, 1180, 1120.

PREPARATION 180

(E)-3-(3,5-Difluorophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 140°-142° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 90%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm 3.85(3H,s),6.22(1H,s), 6.75-6.94 (3H,m), 6.90(2H,dm,J=8.79 Hz), 7.14(2H,dm,J=8.79Hz).

Mass Spectrum (m/z): 290(M⁺), 273, 245.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3600-2400, 1695,1625, 1610, 1595, 1515, 1435, 1295, 1250, 1175, 1125.

PREPARATION 181

Ethyl (Z)-3-(3-Cyanophenyl)-3-(4-methoxyphenyl)acrylate

Prepared as crystals, melting at 105°-106° C. (after recrystallisationfrom hexane), in a yield of 43%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.15(3H,t,J=7.32 Hz), 3.83(3H,s), 4.05(2H,q,J=7.32 Hz), 6.38(1H,s),6.86(2H,dm,J=8.79 Hz), 7.19(2H,dm,J=8.79 Hz), 7.45(1H,ddd,J=7.69, 1.47,1.47 Hz), 7.48-7.52 (1H,m), 7.51(1H,ddd,J=7.69, 7.69, 0.73 Hz),7.68(1H,ddd,J=7.69, 1.47, 1.47 Hz).

Mass Spectrum (m/z): 307(M⁺), 278, 262, 235.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻ 1: 2240, 1715, 1610,1515, 1375, 1280, 1260, 1170, 1030, 835.

PREPARATION 182

(Z)-3-(3-Cyanophenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 193°-194° C. (after recrystallisationfrom a mixture of THF and hexane), in a yield of 8%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 3.83(3H,s),6.34(1H,s), 6.86(2H,dm,J=8.79 Hz), 7.17(2H,dm,J=8.79 Hz),7.44(1H,ddd,J=7.82, 1.47, 1.47 Hz), 7.45-7.50(1H,m), 7.48(1H,dd,J=7.82,7.82 Hz), 7.67(1H, ddd,J=7.82, 1.47, 1.47 Hz).

Mass Spectrum (m/z): 279(M⁺), 262, 234.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3600-2400, 2240,1690, 1600, 1570, 1510, 1425, 1285, 1260, 1180, 1035, 835.

PREPARATION 183

Ethyl (Z)-3-(3-Fluorophenyl)-3-(4-ethoxyphenyl)acrylate

Prepared as an oil, in a yield of 16%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.12(3H,t,J=7.33 Hz), 1.41(3H,t,J=6.96 Hz), 4.038(2H,q,J=6.96 Hz),4.042(2H,q,J=7.33 Hz), 6.32(1H,s), 6.83(2H,dm,J=8.79 Hz),6.91(1H,ddd,J=9.53, 2.56, 1.46 Hz), 6.95-7.02(1H,m),7.07(1H,dddd,J=8.43, 8.43, 2.56, 1.10 Hz), 7.22(2H,dm,J=8.79 Hz),7.34(1H,ddd,J=8.43, 8.43, 5.86 Hz).

Mass Spectrum (m/z): 314(M⁺), 285, 269, 242.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1705, 1600, 1580,1510, 1475, 1370, 1270, 1250, 1160, 1115, 1035.

PREPARATION 184

Ethyl (E)-3-(3-Fluorophenyl)-3-(4-ethoxyphenyl)acrylate

Prepared as an oil, in a yield of 8%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.16(3H,t,J=7.32 Hz), 1.43(3H,t,J=6.83 Hz), 4.07(2H,q,J=6.83 Hz),4.09(2H,q,J=7.32 Hz), 6.26(1H,s), 6.89(2H,dm,J=8.79 Hz),6.94-7.13(3H,m), 7.13(2H,dm,J=8.79 Hz), 7.28(1H,ddd,J=8.30, 8.30, 5.86Hz).

Mass Spectrum (m/z): 314(M⁺), 285, 269, 242.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1605, 1580,1510, 1485, 1475, 1440, 1370, 1240, 1170, 1130, 1035.

PREPARATION 185

(Z)-3-(3-Fluorophenyl)-3-(4-ethoxyphenyl)acrylic acid

Prepared as crystals, melting at 154°-155° C. (after recrystallisationfrom a mixture of THF and hexane), in a yield of 91%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.41(3H,t,J=6.83 Hz), 4.04(2H,q,J=6.83 Hz), 6.28(1H,s),6.83(2H,dm,J=8.79 Hz), 6.90 (1H,ddd,J=9.28, 2.44, 1.46 Hz),6.94-7.00(1H,m), 7.06(1H,dddd,J=8.30, 8.30, 2.44, 0.98 Hz),7.20(2H,dm,J=8.79 Hz), 7.33(1H,ddd,J=8.30, 8.30, 5.86 Hz).

Mass Spectrum (m/z): 286(M⁺), 269, 257, 241.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3600-2400, 1690,1595, 1510, 1435, 1285, 1250, 1175, 1115, 1035.

PREPARATION 186

(E)-3-(3-Fluorophenyl)-3-(4-ethoxyphenyl)acrylic acid

Prepared as crystals, melting at 148°-149° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 95%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.44(3H,t,J=6.83 Hz), 4.07(2H,q,J=6.83 Hz), 6.22(1H,s),6.88(2H,dm,J=8.79 Hz), 6.92-7.00(1H,m), 7.01-7.12(2H,m),7.14(2H,dm,J=8.79 Hz), 7.29(1H,ddd,J=8.30, 8.30, 5.86 Hz). Mass Spectrum(m/z): 286(M⁺), 269, 257, 241.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3600-2400, 1690,1605, 1580, 1510, 1485, 1440, 1285, 1265, 1240, 1170, 1035.

PREPARATION 187

Ethyl (Z)-3-(3-Chloro-5-methylphenyl)-3-(4-methoxyphenyl)acrylate

Prepared as crystals, melting at 83°-85° C. (after recrystallisationfrom hexane), in a yield of 49%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.12(3H,t,J=7.33 Hz), 2.33(3H,s), 3.82(3H,s), 4.05(2H,q,J=7.33 Hz),6.29(1H,s), 6.85(2H,dm,J=8.79 Hz), 6.86-6.90(1H,m), 6.98-7.03(1H,m),7.14-7.20(1H,m), 7.23(2H,dm,J=8.79 Hz).

Mass Spectrum (m/z): 330(M⁺, ³⁵ Cl), 301, 285, 258.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1600, 1575,1510, 1290, 1275, 1250, 1165, 1030, 830.

PREPARATION 188

Ethyl (E)-3-(3-Chloro-5-methylphenyl)-3-(4-methoxyphenyl)acrylate

Prepared as an oil, in a yield of 17%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.17(3H,t,J=7.33 Hz), 2.30(3H,s), 3.85(3H,s), 4.09(2H,q,J=7.33 Hz),6.23(1H,s), 6.90(2H,dm,J=8.79 Hz), 6.95-7.02(1H,m), 7.04-7.09(1H,m),7.13-7.19(1H,m), 7.14(2H,dm,J=8.79 Hz).

mass Spectrum (m/z): 330(M⁺, ³⁵ Cl), 301, 285, 258.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1710, 1610, 1570,1510, 1290, 1280, 1245, 1170, 1140, 1030.

PREPARATION 189

(Z)-3-(3-Chloro-5-methylphenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 190°-192° C. (after recrystallisationfrom a mixture of THF and hexane), in a yield of 93%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 2.33(3H,s),3.82(3H,s), 6.26(1H,s), 6.85(2H,dm,J=8.79 Hz), 6.85-6.90(1H,m),6.96-7.01(1H,m), 7.14-7.20(1H,m), 7.21(2H,dm,J=8.79 Hz).

Mass Spectrum (m/z): 302(M⁺, ³⁵ Cl), 285, 257.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3600-2400, 1690,1600, 1570, 1510, 1280, 1250, 1175, 1030, 830.

PREPARATION 190

(E)-3-(3-Chloro-5-methylphenyl)-3-(4-methoxyphenyl)acrylic acid

Prepared as crystals, melting at 156°-158° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 91%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 2.30(3H,s),3.85(3H,s), 6.18(1H,s), 6.89(2H,dm,J=8.79 Hz), 6.94-6.99(1H,m),7.00-7.06(1H,m), 7.14-7.20(1H,m), 7.14(2H,dm,J=8.79 Hz).

Mass Spectrum (m/z): 302(M⁺,³⁵ Cl), 285, 257.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 3600-2400, 1690,1605, 1570, 1510, 1290, 1245, 1170, 1030, 870, 850, 830.

PREPARATION 191

Ethyl (Z)-3-(3-Chloro-5-methylphenyl)-3-(4-ethoxyphenyl)acrylate

Prepared as an oil, in a yield of 17%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.12(3H,t,J=7.32 Hz), 1.41(3H,t,J=6.96 Hz), 2.33(3H,s), 4.04(2H,q,J=6.96Hz), 4.05(2H, q,J=7.32 Hz), 6.29(1H,s), 6.83(2H,dm,J=8.79 Hz),6.85-6.91(1H,m), 6.98-7.02(1H,m), 7.15-7.19(1H,m), 7.21(2H,dm,J=8.79Hz).

Mass Spectrum (m/z): 344(M⁺,³⁵ Cl), 315, 299, 272.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm¹ : 1705, 1600, 1570,1510, 1475, 1365, 1270, 1250, 1160, 1035, 850, 830.

PREPARATION 192

Ethyl (E)-3-(3-Chloro-5-methylphenyl)-3-(4-ethoxyphenyl)acrylate

Prepared as an oil, in a yield of 6%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.16(3H,t,J=7.32 Hz), 1.43(3H,t,J=6.84 Hz), 2.30(3H,s), 4.07(2H,q,J=6.84Hz), 4.08(2H, q,J=7.32 Hz), 6.22(1H,s), 6.89(2H,dm,J=8.79 Hz),6.95-7.01(1H,m), 7.04-7.09(1H,m), 7.12-7.18(1H,m), 7.12(2H,dm,J=8.79Hz).

Mass Spectrum (m/z): 344(M⁺, ³⁵ Cl), 315, 299, 272.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1705, 1605, 1570,1510, 1475, 1365, 1280, 1240, 1165, 1140, 1110, 1035, 850.

PREPARATION 193

(Z)-3-(3-Chloro-5-methylphenyl)-3-(4-ethoxyphenyl)acrylic acid

Prepared as crystals, melting at 197°-199° C. (after recrystallisationfrom a mixture of THF and hexane), in a yield of 89%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.41(3H,t,J=6.84 Hz), 2.32(3H,s), 4.04(2H,q,J=6.84 ), 6.26(1H,s),6.83(2H,dm,J=9.28 Hz), 6.85-6.91(1H,m), 6.96-7.02(1H,m),7.14-7.20(1H,m), 7.20(2H,dm,J=9.28 Hz).

Mass Spectrum (m/z): 316(M⁺, ³⁵ Cl), 287, 271.

PREPARATION 194

(E)-3-(3-Chloro-5-methylphenyl)-3-(4-ethoxyphenyl)acrylic acid

Prepared as crystals, melting at 163°-165° C. (after recrystallisationfrom a mixture of methylene chloride and hexane), in a yield of 86%.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.44(3H,t,J=6.84 Hz), 2.30(3H,s), 4.07(2H,q,J=6.84 Hz), 6.17(1H,s),6.87(2H,dm,J=8.79 Hz), 6.93-7.00(1H,m), 7.00-7.07(1H,m),7.14-7.20(1H,m), 7.13(2H,dm,J=8.79 Hz).

Mass Spectrum (m/z): 316(M⁺,³⁵ Cl), 287, 271.

PREPARATION 195

1-[(E)-3-(2-Chlorophenyl)-3-(4-methoxyphenyl)acryloyl]piperazine

By similar reaction and purification as those of PREPARATION 111, usinga compound of PREPARATION 76 (5.65 g), there was obtained the titlecompound (6.37 g) as a powder, melting at 108°-110° C.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 1.75(1H,s),2.35-2.45(2H,m), 2.65-2.75(2H,m), 3.25-3.35(2H,m), 3.45-3.55(2H,m),3.82(3H,s), 6.28(1H,s), 6.86(2H,dm,J=8.79 Hz), 7.16-7.36(6H,m).

Elemental Analysis for C₂₀ H₂₁ N₂ O₂ Cl: Calcd.: C,67.32; H,5.93;N,7.85; Cl, 9.93. Found: C,67.09; H,5.81; N,7.81; Cl,10.10.

PREPARATION 196

4-Acetoxy-3,5-dimethoxybenzoic acid

To a mixture of 3,5-dimethoxy-4-hydroxybenzoic acid (3.00 g) and aceticanhydride (30 ml) was dropwise added pyridine (15 ml) with ice-coolingover a 5 minutes period. After stirring at room temperature for 30minutes, the reaction mixture was poured into water and stirred at roomtemperature for 30 minutes followed by extracting thrice with ethylacetate. The combined extract was washed with 10% hydrochloric acid,dried and concentrated. The residue was recrystallized from a mixture ofmethylene chloride and hexane to afford the title compound (3.13 g),melting at 192°-194° C.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 2.36(3H,s),3.90(6H,s), 7.40(2H,s).

Elemental Analysis for C₁₁ H₁₂ O₆ : Calcd.: C,55.00; H,5.04. Found:C,55.02; H,5.04.

PREPARATION 197

Ethyl 3,5-dichlorocinnamate

To a mixture of sodium hydride (0.84 g: 55% dispersion in mineral oil)and tetrahydrofuran (40 ml) was dropwise added a solution of ethyldiethylphosphonoacetate (4.33 g) in tetrahydrofuran (20 ml) withice-cooling of 6° to 12° C. over a 12 minutes period. After stirring atroom temperature for 30 minutes, to the mixture thus obtained wasdropwise added a solution of 3,5-dichlorobenzaldehyde (3.07 g) intetrahydrofuran (20 ml) with ice-cooling of 8° to 11° C. over a 10minutes period. After stirring at room temperature for 4 hours, thereaction mixture was poured into water and extracted twice with ethylacetate. The combined extract was washed with water, dried andconcentrated. The residue was purified by flash column chromatographythrough silica gel (100 g). Fractions eluted with a 99:1 mixture ofhexane and ethyl acetate were collected and worked up to afford thetitle compound (3.33 g), melting at 71°-73° C.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.34(3H,t,J=7.32 Hz), 4.27(2H,q,J=7.32 Hz), 6.43(1H,d,J=16.11 Hz),7.36(1H,t,J=1.95 Hz), 7.38(2H,d,J=1.95 Hz), 7.54(1H,d,J=16.11 Hz).

Mass Spectrum (m/z): 244(M⁺,³⁵ Cl), 216, 199, 171.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1770, 1640, 1580,1560, 1415, 1360, 1310, 1280, 1270, 1170, 1020, 970, 845.

Elemental Analysis for C₁₁ H₁₀ O₂ Cl₂ : Calcd.: C,53.90; H,4.11;Cl,28.93. Found: C,54.01; H,4.16; Cl,28.76.

PREPARATION 198

Ethyl 2,5-dichlorocinnamate

Following the procedure described in PREPARATION 197, but using2,5-dichlorobenzaldehyde (9.74 g), there was obtained the title compound(12.17 g), melting at 34°-36° C.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.35(3H,t,J=7.32 Hz), 4.29(2H,q,J=7.32 Hz), 6.42(1H,d,J=16.12 Hz),7.27(1H,dd,J=8.31, 2.44 Hz), 7.35(1H,d,J=8.30 Hz), 7.59(1H,d,J=2.44 Hz),7.99(1H,d,J=16.12 Hz).

Mass Spectrum (m/z): 244(M⁺,³⁵ Cl), 209, 199.

Elemental Analysis for C₁₁ H₁₀ O₂ Cl₂ : Calcd.: C,53.90; H,4.11;Cl,28.93. Found: C,54.14; H,4.24; Cl,28.77.

PREPARATION 199

Ethyl 2,3-dichlorocinnamate

Following the procedure described in PREPARATION 197, but using2,3-dichlorobenzaldehyde (20.00 g), there was obtained the titlecompound (23.46 g), melting at 69°-70° C.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.35(3H,t,J=7.32 Hz), 4.29(2H,q,J=7.32 Hz), 6.41(1H,d,J=16.12 Hz),7.22(1H,dd,J=8.30, 8.30 Hz), 7.48(1H,dd,J=8.30,1.47 Hz),7.51(1H,dd,J=8.30,1.47 Hz), 8.08(1H, d,J=16.12 Hz).

Mass Spectrum (m/z): 244(M⁺,³⁵ Cl), 209, 199.

Elemental Analysis for C₁₁ H₁₀ O₂ Cl₂ : Calcd.: C,53.90; H,4.11;Cl,28.93. Found: C,54.10; H,4.31; Cl,28.65.

PREPARATION 200

Ethyl 3,5-dimethylcinnamate

The procedure described in PREPARATION 197 was repeated, but using3,5-dimethylbenzaldehyde (11.44 g). The crude product was purified byflash column chromatography through silica gel (300 g). Fractions elutedwith a 9:1 mixture of hexane and ethyl acetate were collected and workedup to afford the title compound (15.22 g).

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:1.33(3H,t,J=7.32 Hz), 2.33(6H,S), 4.26(2H,q,J=7.32 Hz),6.41(1H,d,J=16.12 Hz), 7.02(1H, br.s), 7.14(2H,br.s), 7.63(1H,d,J=16.12Hz).

Mass Spectrum (m/z): 204(M⁺), 189, 175, 159.

Elemental Analysis for C₁₃ H₁₅ O₂ : Calcd.: C,76.44; H,7.90. Found:C,76.67; H,8.14.

PREPARATION 201

1-[(Z)-3-(3,5-Dichlorophenyl)-3-(4-methoxyphenyl)acryloyl]piperazine

By similar reaction and purification as those of PREPARATION 111, usinga compound of PREPARATION 147 (1.00 g), there was obtained the titlecompound (1.07 g) as a powder.

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm: 1.89(1H,s),2.45-2.65(2H,m), 2.65-2.85(2H,m), 3.25-3.45(2H,m), 3.45-3.65(2H,m),3.83(3H,s), 6.33(1H,s), 6.87(2H,dm,J=8.79 Hz), 7.17(2H,d,J=1.95 Hz),7.19 (2H,dm,J=8.79 Hz), 7.35(1H,t,J=1.95 Hz).

Mass Spectrum (m/z): 390(M⁺, ³⁵ Cl), 305, 85.

Infrared Absorption Spectrum ν_(max) (CHCl₃) cm⁻¹ : 1630,1610, 1565,1515, 1465, 1445, 1250, 1180.

Elemental Analysis for C₂₀ H₂₀ N₂ O₂ Cl₂ : Calcd.: C,61.39; H,5.15;N,7.16; Cl,18.12.Found: C,61.44; H,5.39; N,7.04; Cl,17.93.

EXPERIMENT 1

Inhibition of PAF-induced hypotension

The test animals used were Wistar-Imamichi rats, each weighing from 350to 450 g, anesthetized with Inactin (90 mg/kg, intraperitoneally).

Blood pressure was continuously measured throughout the experimentthrough a cannula inserted into the femoral artery. Each drug sample tobe tested was intravenously injected through a cannula inserted into thefemoral vein.

At first, l-C_(16:0) PAF was injected intravenously in amounts of 10ng/kg at each injection at intervals of 5 minutes until the degree ofthe hypotensive response became constant. Then, each drug sample to betested was intravenously injected. After one minute, the same dose ofPAF was administered again. The drug sample was cumulativelyadministered. From its inhibition rate against the PAF-inducedhypotensive effect, the 50% inhibitive dose (ID₅₀) was determined, andis regarded as an index of PAF-antagonist activity. For administration,the PAF was dissolved in physiological saline solution containing 0.25%w/v of bovine serum albumin (BSA). The compounds under test weredissolved in dimethylformamide for use.

In addition to the compounds of the invention that were tested, we alsotested a prior art compound, CV-3988, under the same conditions, so asto show the extent of the improvement in activity achieved by thecompounds of the invention as compared with what is recognised to be oneof the most effective of the available prior art compounds. CV-3988 isdisclosed in U.S. Pat. No. 4,408,052, and is structurally related to PAFitself.

Table 4 below shows the results. In this Table, the compounds of theinvention are identified by the number of the foregoing Example in whichthey were prepared.

                  TABLE 4                                                         ______________________________________                                                            Inhibitory                                                                    effect                                                    Compound of Example ID.sub.50 (mg/kg)                                         ______________________________________                                        1                   0.057                                                     2                   0.039                                                     3                   0.048                                                     4                   0.074                                                     5                   0.054                                                     7                   0.014                                                     8                   0.058                                                     15                  0.022                                                     16                  0.074                                                     17                  0.0083                                                    18                  0.026                                                     25                  0.052                                                     28                  0.039                                                     29                  0.048                                                     30                  0.044                                                     31                  0.0067                                                    33                  0.0078                                                    34                  0.021                                                     35                  0.012                                                     36                  0.039                                                     39                  0.0080                                                    41                  0.0071                                                    42                  0.0050                                                    43                  0.0044                                                    44                  0.0075                                                    45                  0.0066                                                    48                  0.012                                                     49                  0.0080                                                    52                  0.0084                                                    53                  0.0074                                                    56                  0.011                                                     70                  0.0033                                                    71                  0.0074                                                    72                  0.0097                                                    73                  0.0084                                                    74                  0.0055                                                    75                  0.0051                                                    76                  0.0092                                                    77                  0.0037                                                    78                  0.0073                                                    79                  0.0066                                                    80                  0.0065                                                    82                  0.013                                                     83                  0.011                                                     84                  0.0086                                                    85                  0.0061                                                    86                  0.015                                                     87                  0.011                                                     88                  0.092                                                     Prior art compound, CV-3988                                                                       0.42                                                      ______________________________________                                    

EXPERIMENT 2

Inhibitory effect in vitro against PAF-induced blood plateletaggregation

Blood samples were drawn from a rabbit and one part by volume of eachsample was immediately mixed with 1/9 part of a 3.8% w/v aqueoussolution of sodium citrate. The samples were centrifuged at 150×G atroom temperature for 15 minutes to obtain a platelet rich plasma (PRP)fraction from the upper layer. The remains were further centrifuged at1,000×G for 15 minutes to obtain a platelet poor plasma (PPP) fractionfrom the upper layer. The PRP and PPP fractions were mixedappropriately, to obtain a sample in which the final count of bloodplatelets was adjusted to be 6×10⁵ per μl. According to the methodreported by Born et al. [G. V. R. Born et al.: J. Physiol. 62, 67-68(1962)], blood platelet aggregation was determined by an increase inlight transmission measured using an aggregometer. 3 μl of a solution ofthe test compound in dimethyl sulfoxide were added to 272 μl of PRP,and, after 1 minute, 25 μl of a physiological saline solution containingl-C_(16:0) PAF (at a final concentration of 10⁻⁸ ˜3×10⁻⁸ M) were added.Inhibition of aggregation was observed for 5 minutes. At the end of thistime, the inhibition rate was calculated from this value and the valueof PAF-induced aggregation which was observed when dimethyl sulfoxideonly was used without the addition of any test compound. IC₅₀ valueswere calculated from the dose-response curve.

Table 5 below shows the results.

                  TABLE 5                                                         ______________________________________                                                          Inhibitory                                                                    effect                                                      Compound of Example                                                                             IC.sub.50 (M)                                               ______________________________________                                        1                 3.2 × 10.sup.-7                                       2                 2.0 × 10.sup.-7                                       3                 2.2 × 10.sup.-7                                       5                 2.6 × 10.sup.-7                                       15                6.8 × 10.sup.-8                                       17                6.3 × 10.sup.-8                                       28                2.3 × 10.sup.-7                                       29                1.8 × 10.sup.-7                                       30                1.5 × 10.sup.-7                                       31                4.4 × 10.sup.-8                                       33                4.3 × 10.sup.-8                                       35                1.1 × 10.sup.-7                                       36                2.2 × 10.sup.-7                                       37                1.1 × 10.sup.-7                                       40                1.1 × 10.sup.-7                                       41                6.7 × 10.sup.-8                                       45                3.9 × 10.sup.-8                                       49                6.6 × 10.sup.-8                                       52                3.0 × 10.sup.-8                                       53                5.2 × 10.sup.-8                                       70                3.0 × 10.sup.-8                                       71                3.8 × 10.sup.-8                                       73                8.6 × 10.sup.-8                                       74                5.8 × 10.sup.-8                                       75                9.9 × 10.sup.-8                                       76                8.3 × 10.sup.-8                                       77                2.6 × 10.sup.-8                                       78                2.9 × 10.sup.-8                                       80                2.8 × 10.sup.-8                                       81                3.1 × 10.sup.-8                                       82                9.9 × 10.sup.-9                                       87                6.5 × 10.sup.-8                                       ______________________________________                                    

EXPERIMENT 3

Inhibitory effect of PAF-receptor binding

Blood samples were drawn from the heart of a rabbit. 1 part by volume ofeach sample was mixed immediately with 1/9 part of 0.77M solution ofdisodium ethylenediaminetetraacetate. After a similar procedure to thatdescribed in Experiment 2, a precipitated blood platelet sample wasobtained. This blood platelet sample was washed, and, after repeatedfreezing and thawing for cellular breakdown, it was laid on top ofdouble layers consisting of 0.25M and 1.5M sucrose solutions. Bycentrifugation at 63,500×G, for 2 hours at 4° C., the fraction obtainedfrom the interface between the 0.25M and 1.5M sucrose solutions wascollected and is regarded as a PAF-receptor membrane fraction. Areceptor binding experiment was conducted according to a method verysimilar to that reported by Hwang et al. [San-Bao Hwang et al.: J. Biol.Chem. 260, 15639-15645 (1985)]. The specific binding of ³ H-PAF wasmeasured using a Wattman GF/C filter. A test compound was dissolved indimethyl sulfoxide and diluted 100 fold with a buffer solutioncontaining 0.5% bovine serum albumin. Nine parts by weight of thesolution, for a receptor binding experiment, was mixed with one part ofthe test compound solution prepared above. The percent inhibition of thespecific binding was plotted for a log concentration of the testcompound, and the 50% inhibitory concentration (IC₅₀) was calculatedfrom the linear line connecting all the plotted points.

The results are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                                           Inhibition of receptor                                     Compound of Example                                                                              binding (IC.sub.50, M)                                     ______________________________________                                        1                  4.7 × 10.sup.-8                                      5                  4.7 × 10.sup.-8                                      15                 4.3 × 10.sup.-8                                      31                 1.4 × 10.sup.-8                                      41                 1.7 × 10.sup.-7                                      42                 2.0 × 10.sup.-8                                      43                 1.3 × 10.sup.-8                                      44                 1.5 × 10.sup.-8                                      45                 1.6 × 10.sup.-8                                      49                 2.1 × 10.sup.-8                                      56                 3.5 × 10.sup.-8                                      72                 2.6 × 10.sup.-8                                      75                 2.3 × 10.sup.-8                                      77                 1.4 × 10.sup.-8                                      81                 3.2 × 10.sup.-8                                      83                 1.4 × 10.sup.-8                                      84                 4.0 × 10.sup.-8                                      85                 2.0 × 10.sup.-8                                      87                 7.6 × 10.sup.-8                                      Prior art compound, CV-3988                                                                      1.6 × 10.sup.-6                                      ______________________________________                                    

As can be seen from this table, the novel N-acryloylpiperazinederivatives of the present invention have an excellent PAF-antagonistactivity.

EXPERIMENT 4

Acute toxicity

Each of the compounds prepared as described in Examples 2, 7 and 15 wasseparately administered orally in a dose of 300 mg/kg to each of a groupof 3 male ddy mice (5 weeks old). The mice were observed for a period ofone week, during which time all mice survived, indicating that thecompounds of the present invention have a very low toxicity.

FORMULATION 1

Tablets

The composition was as follows:

    ______________________________________                                        Compound of Example 3   50     mg                                             Lactose                 98     mg                                             Corn starch             30     mg                                             Microcrystalline cellulose                                                                            20     mg                                             Magnesium stearate      2      mg                                                                     200    mg                                             ______________________________________                                    

All of the above ingredients, except for the magnesium stearate, wereblended for 30 minutes, after which the magnesium stearate was addedthrough a screen, and the mixture was blended for a further 5 minutes.The mixture was then compressed to form tablets of diameter 8 mm.

FORMULATION 2

Capsules

The composition was as follows:

    ______________________________________                                        Compound of Example 3  50     mg                                              Lactose                98     mg                                              Corn starch            50     mg                                              Magnesium stearate     2      mg                                                                     200    mg                                              ______________________________________                                    

All of the above ingredients were blended for 5 minutes, after which themixture was filled into No. 3 capsules.

FORMULATION 3

Granules

The composition was as follows:

    ______________________________________                                        Compound of Example 3  50     mg                                              Lactose                730    mg                                              Corn starch            200    mg                                              Hydroxypropyl cellulose                                                                              20     mg                                                                     1000   mg                                              ______________________________________                                    

The first three of the above ingredients were mixed, and then themixture was moistened with a 10% aqueous solution of the hydroxypropylcellulose. The moistened mixture was then granulated by passing itthrough a basket with an extruder of diameter 0.5 mm. The granules weredried at 60° C. and sized through a 16 mesh screen (Tyler standardmesh).

FORMULATION 4

Suppositories

50 mg of the Compound of Example 3 were dispersed in 1950 mg of Witepsol(trade mark) at 50° C. and poured into an appropriate mold.

FORMULATION 5

Syrups

The composition was as follows:

    ______________________________________                                        Compound of Example 3    1      g                                             Sucrose                  50     g                                             Carboxymethylcellulose sodium                                                                          0.25   g                                             Citric acid              0.15   g                                             Sodium citrate           1      g                                             Sodium benzoate          0.5    g                                             Purified Water           100    ml                                            ______________________________________                                    

The sucrose, citric acid, sodium citrate and sodium benzoate weredissolved in purified water; the carboxymethylcellulose sodium wasdispersed in the resulting solution with the active compound, and thenthe volume was adjusted with more purified water.

FORMULATION 6

Injections

The composition was as follows:

    ______________________________________                                        Compound of Example 3     1.0    mg                                           Propylene glycol          150.0  mg                                           Polysorbate 80            0.5    mg                                           Sodium dihydrogen phosphate (dihydrate)                                                                 1.6    mg                                           Disodium hydrogen phosphate (anhydrous)                                                                 1.4    mg                                           Purified water for injection                                                                            1.0    ml                                           ______________________________________                                    

The active compound was dissolved in a mixture of the propylene glycoland the Polysorbate 80, and the resulting solution was mixed with waterfor injection. The phosphates were then dissolved in the solution andthe volume was adjusted. The solution was filled into an ampoule, whichwas then sealed and sterilized at 121° C. for 20 minutes.

We claim:
 1. A method of treating or preventing a PAF-mediated pathologyin a mammal suffering from or susceptible to said PAF-mediatedpathology, said PAF-mediated pathology selected from the groupconsisting of myocardial infarction, angina pectoris, systemicanaphylaxis, gastric ulceration, intestinal ulceration and organtransplantation rejection by administering to said mammal an effectiveamount of a PAF antagonist compound of the formula (I) ##STR14##wherein: R¹ and R² are the same or different, and each represents --R⁵or a group having the formula --CH═CH--R⁵ or --C═C--R⁵,wherein R⁵represents a C₆ -C₁₄ carboxylic aryl group which is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (a), defined below, or an aromatic heterocyclic grouphaving from 5 to 14 ring atoms, of which from 1 to 5 are hetero-atomsselected from the group consisting of nitrogen, oxygen and sulfurhetero-atoms, said heterocyclic group being unsubstituted or having atleast one substituent selected from the group consisting of substituents(a), defined below; R³ represents a hydrogen atom, a C₁ -C₆ alkyl group,a cyano group, or said --R⁵ ; X represents an oxygen atom or a sulfuratom; A represents a 1,4-piperazin-1,4-diyl group or a1,4-homopiperazin-1,4-diyl group; B represents a C₁ -C₆ alkylene group,a carbonyl group, a thiocarbonyl group, a sulfinyl group or a sulfonylgroup; R⁴ represents an unsubstituted phenyl group or a substitutedphenyl group having from 1 to 5 substituents selected from the groupconsisting of substituents (a) and substituents (b), definedbelow:substituents (a): C₁ -C₂₂ alkyl groups; C₁ -C₂₂ alkoxy groups; C₁-C₆ haloalkyl groups; hydroxy groups; C₁ -C₄ alkylenedioxy groups; C₁-C₆ aliphatic carboxylic acyloxy groups; substituted C₁ -C₂₂ aliphaticcarboxylic acyloxy groups having at least one substituent selected fromthe group consisting of substituents (c), defined below; C₇ -C₁₅carbocyclic aromatic carboxylic acyloxy groups; substituted C₇ -C₁₅carbocyclic aromatic carboxylic acyloxy groups having at least onesubstituent selected from the group consisting of substituents (d),defined below; C₈ -C₁₅ aralkyloxycarbonyloxy groups in which the arylpart is unsubstituted or has at least one substituent selected from thegroup consisting of substituents (d), defined below; C₁ -C₆alkanesulfonyloxy groups in which the alkane part is unsubstituted orhas at least one substituent selected from the group consisting ofsubstituents (c), defined below; arylsulfonyloxy groups in which thearyl part is unsubstituted or has at least one substituent selected fromthe group consisting of substituents (d), defined below; halogen atoms;and nitro groups;substituents (b): C₁ -C₆ alkylsulfonyl groups; C₁ -C₆alkylsulfinyl groups; and C₁ -C₆ alkylthio groups;substituents (c): C₁-C₆ alkyl groups; C₁ -C₆ haloalkyl groups, halogen atoms; C₁ -C₆ alkoxygroups; and (C₁ -C₆ alkanoyloxy)methoxycarbonyl groups;substituents (d):C₁ -C₆ alkyl groups; C₁ -C₆ alkoxy groups; halogen atoms; unsubstitutedC₆ -C₁₀ aryl groups; nitro groups; and (C₁ -C₆ alkoxy)carbonyl groups;and pharmaceutically acceptable salts thereof.
 2. The method of claim 1,wherein said PAF antagonist compound is a compound selected from thegroup consistingof1-(3-(4-methoxyphenyl)-3-(2,5-dichlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-ethoxyphenyl)-3-(3,5-dichlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3-chloro-5-methylphenyl)acryloyl)-4-3,4,5-trimethoxybenzoyl)piperazine,1-(3-(3-propoxyphenyl)-3-(3-chlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-propoxyphenyl)-3-(3-chlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(3-methoxyphenyl)-3-(2-chlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3-bromophenyl)acryloyl)4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3-fluorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3-trifluoromethylphenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(3-propoxyphenyl)-3-phenylacryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(2,4-dichlorophenyl)acryloyl-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(2,6-dichlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(2,3-dichlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3,5-dimethylphenyl)acryloyl)-4-3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-ethylphenyl)-3-(3-chlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3,5-di-trifluoromethylphenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-ethylphenyl)-3-(3,5-dichlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3,5-difluorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-ethoxyphenyl)-3-(3-fluorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-ethoxyphenyl)-3-(3-chloro-5-methylphenyl)acryloyl)-4-(3,4,5-trimethoxyhbenzoyl)piperazine,1-(3-(2-chlorophenyl)-3-(4-methoxyphenyl)acryloyl)-4-(4-acetoxy-3,5-dimethoxybenzoyl)piperazine,1-(3-(2-chlorophenyl)-3-(4-methoxyphenyl)acryl)-4-(3,5-dimethoxy-4-hydroxybenzoyl)piperazine and1-(3-(4-methoxyphenyl)-3-(3-trifluoromethylphenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)hexahydro-1H-1,4-diazepine.3. The method of claim 2, wherein the PAF antagonist compound is in theform of the Z-isomer.
 4. The method of claim 2, wherein the PAFantagonist compound is in the form of the E-isomer.
 5. A method for thetreatment or prophylaxis of psoriasis, nephritis, asthma, inflammationor shock comprising administering an amount of a PAF antagonist compoundto an animal in need thereof sufficient to effect treatment orprophylaxis of psoriasis, nephritis, asthma, inflammation or shock,wherein said PAF antagonist compound is a compound of the formula (I)##STR15## wherein: R¹ and R² are the same or different, and eachrepresents a group having the formula --R⁵, --CH═CH--R⁵ or--C.tbd.C--R⁵,wherein R⁵ represents a C₆ -C₁₄ carboxylic aryl groupwhich is unsubstituted or has at least one substituent selected from thegroup consisting of substituents (a), defined below, or an aromaticheterocyclic group having from 5 to 14 ring atoms, of which from 1 to 5are hetero-atoms selected from the group consisting of nitrogen, oxygenand sulfur hetero-atoms, said heterocyclic group being unsubstituted orhaving at least one substituent selected from the group consisting ofsubstituents (a), defined below; R³ represents a hydrogen atom, a C₁ -C₆alkyl group, a cyano group, or a group having the formula --R⁵, in whichR⁵ is as defined above; X represents an oxygen atom or a sulfur atom; Arepresents a 1,4-piperazin-1,4-diyl group or a1,4-homopiperazin-1,4-diyl group; B represents a C₁ -C₆ alkylene group,a carbonyl group, a thiocarbonyl group, a sulfinyl group or a sulfonylgroup; R⁴ represents an unsubstituted phenyl group or a substitutedphenyl group having from 1 to 5 substituents selected from the groupconsisting of substituents (a) and substituents (b), definedbelow;substituents (a): C₁ -C₂₂ alkyl groups; C₁ -C₂₂ alkoxy groups; C₁-C₆ haloalkyl groups; hydroxy groups; C₁ -C₄ alkylenedioxy groups; C₁-C₆ aliphatic carboxylic acyloxy groups; substituted C₁ -C₂₂ aliphaticcarboxylic acyloxy groups having at least one substituent selected fromthe group consisting of substituents (c), defined below; C₇ -C₁₅carbocyclic aromatic carboxylic acyloxy groups; substituted C₇ -C₁₅carbocyclic aromatic carboxylic acyloxy groups having at least onesubstituent from the group consisting of substituents (d), definedbelow; C₈ -C₁₅ aralkyloxycarbonyloxy groups in which the aryl part isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (d), defined below; C₁ -C₆ alkanesulfonyloxygroups in which the alkane part is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (c),defined below; arylsulfonyloxy groups in which the aryl part isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (d), defined below; halogen atoms; and nitrogroups;substituents (b): C₁ -C₆ alkylsulfonyl groups; C₁ -C₆alkylsulfinyl groups; and C₁ -C₆ alkylthio groups;substituents (c): C₁-C₆ alkyl groups; C₁ -C₆ haloalkyl groups; halogen atoms; C₁ -C₆ alkoxygroups; and (C₁ -C₆ alkanoyloxy)methoxycarbonyl groups;substituents (d):C₁ -C₆ alkyl groups; C₁ -C₆ alkoxy groups; halogen atoms; unsubstitutedC₆ -C₁₀ aryl groups; nitro groups; and (C₁ -C₆ alkoxy)carbonylgroups;and pharmaceutically acceptable salts thereof.
 6. The method ofclaim 5, wherein said PAF antagonist compound is a compound selectedfrom the group consisting of1-(3-(4-methoxyphenyl)-3-(2,5-dichlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-ethoxyphenyl)-3-(3,5-dichlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3(4-methoxyphenyl)-3-(3-chloro-5-methylphenyl)acryloyl)-4-3,4,5-trimethoxybenzoyl)piperazine,1-(3-(3-propoxyphenyl)-3-(3-chlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-propoxyphenyl)-3-(3-chlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(3-methoxyphenyl)-3-(2-chlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3-bromophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3-fluorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-trifluoromethylphenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(3-propoxyphenyl)-3-phenylacryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(2,4-dichlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(2,6-dichlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(2,3-dichlorophenyl(acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3,5-dimethylphenyl)acryloyl)-4-3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-ethylphenyl)-3-(3-chlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3,5-di-trifluoromethylphenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-ethylphenyl)-3-(3,5-dichlorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-methoxyphenyl)-3-(3,5-difluorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-ethoxyphenyl)-3-(3-fluorophenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(4-ethoxyphenyl)-3-(3-chloro-5-methylphenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)piperazine,1-(3-(2-chlorophenyl)-3-(4-methoxyphenyl)acryloyl)-4-(4-acetoxy-3,5-dimethoxybenzoyl)piperazine,1-(3-(2-chlorophenyl)-3-(4-methoxyphenyl)acryl)-4-(3,5-dimethoxy-4-hydroxybenzoyl)piperazineand1-(3-(4-methoxyphenyl)-3-(3-trifluoromethylphenyl)acryloyl)-4-(3,4,5-trimethoxybenzoyl)hexahydro-1H-1,4-diazepine.7. The method of claim 5, wherein the PAF antagonist compound is in theform of the Z-isomer.
 8. The method of claim 5, wherein the PAFantagonist compound is in the form of the E-isomer.